急性髓系白血病M2b型诱导分化和凋亡的研究
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摘要
目的：急性白血病M2b型(AML-M2b)由染色体易位产生的AML1-ETO融合蛋白异常募集组蛋白脱乙酰化酶(HDAC)从而抑制AML1靶基因的转录是关键的致病机制，并且DNA甲基化和组蛋白脱乙酰化两个重要的转录抑制机制内部存在着十分密切的关联。探讨HDAC抑制剂苯丁酸钠(PB)联合DNA甲基化抑制剂5-杂氮脱氧胞苷(5-Aza-CdR)阻断AML1-ETO的生物学功能，消除AML1-ETO的转录抑制，诱导AML-M2b白血病细胞分化和凋亡作用。
材料和方法：体外实验应用MTT比色法观察PB或与5-Aza-CdR联合对细胞的生长抑制作用，普通光学显微镜观察细胞形态改变，流式细胞术分析细胞周期和检测髓系分化抗原的表达，Annexin V标记、DNA凝胶电泳和流式细胞术分析细胞凋亡。建立Kasumi-1细胞裸鼠移植瘤模型，研究PB对Kasumi-1细胞裸鼠体内致瘤性的影响；评价PB与5-Aza-CdR联合对裸鼠移植瘤的疗效，研究体内作用机制。
结果：①PB抑制AML-M2b白血病细胞系和原代细胞生长，降低细胞的自我更新能力，使细胞阻滞于G0／G1期，诱导髓系分化抗原CD11b、CD13的表达和细胞凋亡，并且上述作用呈剂量依赖性和时间依赖性。细胞凋亡经过激活Caspase-3途径。②低剂量5-Aza-CdR可以增强PB诱导细胞分化作用，使细胞阻滞于G2／M期；高剂量5-Aza-CdR增强PB对Kasumi-1细胞的生长抑制作用和诱导凋亡作用。③通过裸鼠移植瘤模型证实Kasumi-1经PB体外培养后其致瘤性降低。④PB体内用药可以抑制Kasumi-1细胞裸鼠移植瘤生长，抑制率达49.07％。诱导移植瘤细胞周期阻滞、分化和凋亡，并抑制肿瘤血管新生，肿瘤微血管密度减低。⑤5-Aza-CdR增强PB体内抗肿瘤活性，肿瘤生长抑制率达到87.46％，发生凋亡和抑制血管新生均明显增加。
结论：体外和体内实验均证明脱乙酰化酶抑制剂PB能够抑制AML-M2b白血病细胞生长和自我更新能力，使细胞阻滞于G0／G1期；诱导细胞部分分化和凋亡；DNA甲基化抑制剂5-Aza-CdR增强PB的抗
Dysregulation of histone acetylation has been demonstrated in several hematological neoplasias. It has been reported that a positive interaction between DNA methylation and histone deacetylation takes place to inhibit transcription. In t(8;21) AML, a stable association of AML1/ETO fusion protein with the nuclear histone deacetylase complex (HDAC) is crucial to repressing transcription of AMLl target genes and blocking differentiation of hematopoietic precursors. Phenylbutyrate (PB) is a competitive inhibitor of HDAC1. 5-aza-2'-deoxycytidine (5-Aza-CdR) is a potent inhibitor of DNA methylation. We investigated whether PB alone and combination with 5-Aza-CdR could reverse transcription repression and induce AML1/ETO cells to differentiate and undergo apoptosis.
Cells from the AML1/ETO cell line, Kasumi-1, were treated with PB in suspension culture for 3 days. Incubation of Kasumi-1 cells with PB caused a dose-dependent inhibition of proliferation, with an IC50 of 2.64mM. The proliferation data were also confirmed by colony formation assays. PB also induced a time- and dose-dependent increase in expression of myeloid cell surface proteins CD11b and CD13. By flow cytometric analysis, PB treatment led to a progressive decline in the fraction of S-phase cells and an increase in G0-G1 cells. The induction of apoptosis by PB was demonstrated by annexin V binding coupled with propidium staining, with a dose-dependent increase in early apopotosis as confirmed by DNA ladder assays. Morphological changes of monocytic differentiation and apoptosis were seen by Wright-Giemsa staining. We also evaluated the biological response to PB of primary t(8;21) AML cells. Treatment with PB for 2 days resulted in a dose-dependent reduction in primary AML cell growth as measured by MTT assays, with an IC50 of 3.1mM. After exposure to PB, expression of myeloid cell surface proteins CD11b and CD13 was increased and apoptosis was induced. The combination of PB with 5-Aza-CdR produced a greater inhibition of growth than PB alone, with an IC50
材料和方法：体外实验应用MTT比色法观察PB或与5-Aza-CdR联合对细胞的生长抑制作用，普通光学显微镜观察细胞形态改变，流式细胞术分析细胞周期和检测髓系分化抗原的表达，Annexin V标记、DNA凝胶电泳和流式细胞术分析细胞凋亡。建立Kasumi-1细胞裸鼠移植瘤模型，研究PB对Kasumi-1细胞裸鼠体内致瘤性的影响；评价PB与5-Aza-CdR联合对裸鼠移植瘤的疗效，研究体内作用机制。
结果：①PB抑制AML-M2b白血病细胞系和原代细胞生长，降低细胞的自我更新能力，使细胞阻滞于G0／G1期，诱导髓系分化抗原CD11b、CD13的表达和细胞凋亡，并且上述作用呈剂量依赖性和时间依赖性。细胞凋亡经过激活Caspase-3途径。②低剂量5-Aza-CdR可以增强PB诱导细胞分化作用，使细胞阻滞于G2／M期；高剂量5-Aza-CdR增强PB对Kasumi-1细胞的生长抑制作用和诱导凋亡作用。③通过裸鼠移植瘤模型证实Kasumi-1经PB体外培养后其致瘤性降低。④PB体内用药可以抑制Kasumi-1细胞裸鼠移植瘤生长，抑制率达49.07％。诱导移植瘤细胞周期阻滞、分化和凋亡，并抑制肿瘤血管新生，肿瘤微血管密度减低。⑤5-Aza-CdR增强PB体内抗肿瘤活性，肿瘤生长抑制率达到87.46％，发生凋亡和抑制血管新生均明显增加。
结论：体外和体内实验均证明脱乙酰化酶抑制剂PB能够抑制AML-M2b白血病细胞生长和自我更新能力，使细胞阻滞于G0／G1期；诱导细胞部分分化和凋亡；DNA甲基化抑制剂5-Aza-CdR增强PB的抗
Dysregulation of histone acetylation has been demonstrated in several hematological neoplasias. It has been reported that a positive interaction between DNA methylation and histone deacetylation takes place to inhibit transcription. In t(8;21) AML, a stable association of AML1/ETO fusion protein with the nuclear histone deacetylase complex (HDAC) is crucial to repressing transcription of AMLl target genes and blocking differentiation of hematopoietic precursors. Phenylbutyrate (PB) is a competitive inhibitor of HDAC1. 5-aza-2'-deoxycytidine (5-Aza-CdR) is a potent inhibitor of DNA methylation. We investigated whether PB alone and combination with 5-Aza-CdR could reverse transcription repression and induce AML1/ETO cells to differentiate and undergo apoptosis.
Cells from the AML1/ETO cell line, Kasumi-1, were treated with PB in suspension culture for 3 days. Incubation of Kasumi-1 cells with PB caused a dose-dependent inhibition of proliferation, with an IC50 of 2.64mM. The proliferation data were also confirmed by colony formation assays. PB also induced a time- and dose-dependent increase in expression of myeloid cell surface proteins CD11b and CD13. By flow cytometric analysis, PB treatment led to a progressive decline in the fraction of S-phase cells and an increase in G0-G1 cells. The induction of apoptosis by PB was demonstrated by annexin V binding coupled with propidium staining, with a dose-dependent increase in early apopotosis as confirmed by DNA ladder assays. Morphological changes of monocytic differentiation and apoptosis were seen by Wright-Giemsa staining. We also evaluated the biological response to PB of primary t(8;21) AML cells. Treatment with PB for 2 days resulted in a dose-dependent reduction in primary AML cell growth as measured by MTT assays, with an IC50 of 3.1mM. After exposure to PB, expression of myeloid cell surface proteins CD11b and CD13 was increased and apoptosis was induced. The combination of PB with 5-Aza-CdR produced a greater inhibition of growth than PB alone, with an IC50
引文
1. Grunstein M. Histone acetylation and chromatin structure and transcription. Nature 1997; 389: 349-52.
2. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukemia. Nature 1998; 391: 815-8.
3. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukemia. Nature 1998; 391: 811-4.
4. Yoshida M, Kijima M, Akita M, Beppu T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 1990; 265: 17174-9.
5. Newmark HL, Lupton JR, Young CW. Butyrate as a differentiating agent: pharmacokinetics, analogues and current status. Cancer Lett 1994; 78: 1-5.
6. Carducci M, Bowling MK, Eisenberger M, Sinibaldi V, Chen T, Nor D, et al. Phenylbutyrate (PB) for refractory solid tumors: phase I clinical and pharmacologic evaluation of intravenous and oral PB. Anticancer Res 1997; 17: 3972-3.
7. Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci U S A 1998; 95: 10860-5.
8. Wang L, Hiebert SW. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene 2001; 20: 3716-25.
9. Kass SD, Pruss D, and Wolffe AP. How dose NDA methylation repress transcription?Trends Genet 1997; 13: 444-9.
10. Pinto A, Attadia VV, Fusco LA, et al. 5-Aza-2'-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemia. Blood 1984; 64: 922-9.
11. Momparler RL, Dore BT, Momparler LF, et al. Effect of 5-Aza-2'-deoxycytidine and retinoic acid on differentiation and c-myc expression in HL-60 myeloid leukemic cells. Cancer Lett 1990; 54: 21-8.
12. Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MeCP2 involves a histone deacetylase to reprss transcroption. Nat Genet 1998; 19: 187-91.
13. Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393: 386-9.
14. Weidner N, Semple JP, Welch WR, et al. Tumor angioangesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med 1991; 324: 1-8.
15. Davie JR. Covalent modifications of histones: expression from chromatin templates. Curr Opin Genet Dev 1998; 8: 173-8.
16. Kouzarides T. Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev 1999; 9: 40-8.
17. Redner RL, Wang J, Liu JM. Chromatin remodeling and leukemia: new therapeutic paradigms. Blood 1999; 94: 417-428.
18. Warrell RP Jr, He LZ, Richon V, et al. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998; 90: 1621-5.
19. Ferrara F, Vecchio LD. Acute myeloid leukemia with t(8;21)/AML1/ETO: a distinct biological and clinical entity. Haematologica 2002; 87: 306-19.
20. Lutterbach B, Hiebert SW. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene 2000; 245: 223-35.
21. Speck NA, Stacy T, Wang Q, et al. Core-binding factor: a central player in hematopoiesis and leukemia. Cancer Res 1999; 59: 1789-93.
22. Uchida H, Zhang J, Nimer SD. AML1A and AML1B can transactivate the human IL-3 promoter. J Immunol 1997; 158: 2251-8.
23. Prosser H.M, WottonD, Gegonne A., et al. A phorbol ester response element within the human T-cell receptor O-chain enhancer. Proceedings of the National Academy of Sciences of the United States of America 1992; 89: 9934-38.
24. Takahashi A, Satake M, Yamaguchi-Iwai Y, et al. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood1995; 86: 607-16.
25. Wotton D, Ghysdael J, Wang S,et al. Cooperative binding of Ets-1 and core binding factor to DNA.Molecular and Cellular Biology 1994; 14, 840-50.
26. Zhang DE, Hohaus S, Voso MT, et al. (b) Function of PU. 1(Spi- 1), C/EBP, and AML1 in early myelopoiesis: regulation of multiple myeloid CSF receptor promoters. Current Topics in Microbiology and Immunology 1996211, 137-47.
27. Lutterbach B, Westendorf JJ, Linggi B, et al. A mechanism of transcriptional repression by AML1, the target of multiple chromosome translocations in leukemia. J Biol Chem 2000; 275: 651-6.
28. Lutterbach B, Westendorf JJ, Linggi B, et al. () ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Molecular and Cellular Biology, 1998; 18: 7176-84.
29. Wang J, Wang M. & Liu J.M. Transformation properties of the ETO gene, fusion partner in t(8;21) leukemias. Cancer Rese 1997; 57: 2951-5.
30. Gelmetti V, Zhang J, Fanelli M., et al. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Molecular and Cellular Biology, 1998; 18: 7185-91.
31. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis. Trends Genet 2000; 16: 168-74.
32. Momparler RL, Bovenzi V. DNA methylation and cancer. J Cell Physiol 2000; 183: 145-54.
33. Rivard GE, Momparler RL, Demers J, et al. Phase I study on 5-aza-2'-deoxycytidine in children with acute leukemia. Leuk Res 1981; 5: 453-62.
34. Cameron EE, Kurtis E, Myohanen BS, et al. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 1999; 21: 103-7.
35. Asou H, Tashiro S, Hamamoto K, et al. Establishment of a human acute myeloid leukemia cell line (Kasumi-1) with 8;21 chromosome translocation. Blood 1991; 77: 2031-6.
36. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors:inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst,2000, 92: 1210-1216.
37. Mulloy JC, Cammenga J, Mackenzie KL, et al. The AML1-ETOfusion protein promotes the expansion of human hematopoietic ceils. Blood 2002; 99: 15-23.
38. Kurokawa M, Tanaka T, Tanaka K, et al. Overexpression of the AML1 protooncoprotein in NIH3T3 cells leads to neoplastic transformation depending on the DNA-binding and transactivational potencies. Oncogene 1996; 12: 883-92.
39. Westendorf JJ, Yamamoto CM, Lenny N, et al. The t(8;21) fusion product, AML1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Molecular and Cellular Biology. 1998; 18: 322-33.
40. Sakakura C, Yamaguchi-Iwai Y, Satake M, et al. Growth inhibition and induction of differentiation of t(8;21) acute myeloid leukemia cells by the DNA-binding domain of PEBP2 and the AML1/MTG8(ETO)-specific antisence loigonucleotide. Proc. Natl. Acad. Sci. 1994; 91: 11723-7.
41. Rhoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood 2000; 96: 2108-15.
42. Wang JX, Saunthararajah Y, Redne RL, et al. Inhitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res, 1999, 59: 2766-2769.
43. Gore SD, Samid D, Weng LJ. Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on primary neoplastic myeloid cells. Clin Cancer Res. 1997, 3: 1755-1762.
44. Van Lint C, Emiliani S, Verdin E. The expression of a small fraction of cellular gene is changed in response to histone hyperacetylation. Gene Expr. 1996; 5: 245-4.
45. Klisvic MI, Maghraby EA, Parthun MR, et al. Depsipeptide (FR901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1-ETO-positive leukemic cells. Leukemia 2003; 17: 350-8.
46. Da Silva N, Meyer-Monard S, Menot ML, Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO. Hematol J. 2000; 1(5): 316-28.
47. Almenara J, Rosato R, Grant S. synergistic induction of mitochondrial damage and apotosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 2002; 16: 1331-43.
48. Rahmani M, Dai Y, Grant S. The histone deacetylase inhibitor sodium butyrate interacts synergistically with phorbol myristate acetate (PMA) to induce mitochondrial damage and apotosis in human leukemia cells through a tumor necrosis factor-alpha-mediated process. Exp cell Res 2002; 277: 31-47.
49. Bernhard D, Skavortsov S, Tinhofer I, et al. Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts. Cell Death Differ 2001; 8: 1014-21.
50. Sawa H, Murakami H, Ohshima Y, et al. Histone histone deacetylase inhibitor sodium butyrate and trichostatin A induce apoptosis through an increase of the bc1-2-related protein Bad. Brain Tumor Pathol 2001; 18: 109-14.
51. Aron JL, Parthun MR, Marcucci G, et al. Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase-8-mediated apotosis and downregulation of c-FLIP protein. Blood 2003;
52. Ferreira R, Naguibneva I, Mathieu M, et al. Cell cycle-dependent recruitment of HDAC-1 correlates with deacetylation of histone H4 on an Rb-E2F target promoter. EMBO 2001; 9: 794-9.
53. Brehm A, Miska EA, McCance DJ, et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 1998; 391: 597-601.
54. Brehm A, Miska EA, Reid J, et al. The cell cycle-regulating transcription factors E2F-RB. Br J Cancer suppl 1 1999; 80: 38-41.
55. Richon VM, Sandhoff TW, Rifkind RA, et al. Histone deacetylase inhibitor selectively induces p21~(WAF1) expression and gene-associated Histonedeacetylation. PNAS 2000; 97: 10014-9.
56. DiGiuseppe D, Weng LJ, Yu KH, et al. Phenylbutyrate-induced G1 arrest and apoptosis in myloid leukemia cells: structure-function analysis. Leukemia, 1999, 13: 1243-53.
57. Sowa Y. Sakai T. Butyrate as a model for "gene-regulating chemoprevention and chemotherapy". Biofactors 2000; 12: 283-7.
58. Rosato RR, Almenara JA, Cartee L, et al. The cyclin-dependent kinase inhibitor flavopiridol disrupts sodium butyrate-induced p21WAF1/CIP1 expression and maturation while reciprocally potentiating apoptosis in human leukemia cells. Mol Cancer Ther 2002; 1: 252-66.
59. Sasakawa Y, Naoe Y, Inoue T, et al. Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem Pharmacol 2002; 64: 1079-90.
60. DeSchepper S, Bruwiere H, Verhulst T, et al. Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degredation of survivin. J Pharmacol Exp Ther 2003; 304: 881-8.
61. Lavelle D, Chen YH, Hankewych M, et al. Histone deacetylase inhibitors increase p21WAF1 and induce apoptosis of human myeloma cell lines independent of decreased IL-6 receptor expression. Am J Hematol, 2001; 68: 170-8.
62. Pili R, Kruszewski MP, Hager BW, et al. Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis. Cancer Reser 2001; 61: 1477-85.
63. Kim MS et al. Histona deacetyieses induce angiogenesis by negative regulation of tumor suppressor genes. Nature Mad, 2001; 7: 437-43.
64. Kwen HJ et al. HLstona deasetylese inhibitor FK228 inhibits hypoxia-inducad tumor angiogenasis. Nature Med.(in the press).
65. Gore SD, Miller CB, Weng LJ, et al. Improved hematopoiesis in patients with myelodysplasetic syndromes (MDS) and acute myeloid leukemia (AML) following administration of the putative differentiating agent sodium phenylbutyrate (SPB). Blood 1996; 88(suppll)582a.
66. Niitsu N, Hayashi Y, Sugita K, et al. Sensitization by 5-Aza-2'-deoxycytidine of leukemia cells with MLL abnormalities toinduction of differentiation by all-trans retinoic acid and 1α,25-dihydroxyvitamin D3. British J Haematol 2001; 112: 315-26.
67. Eden S, hashimshony T, Keshet I, et al. DNA methylation models histone acetylation. Nature 1998; 394-42.
68. Zou WG, Lakshmanan RR, Beal MD, et al. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Resear 2001; 61: 1327-33.
69. Shaker S, Bernstein M, Momparler LF, et al. Preclinical evaluation of antineoplastic activity of inhitors of DNA methylation (5-Aza-2'-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) in combination against myeloid leukemia cells. Leukemia Research 2003; 27: 437-44.
1. Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999; 98: 285-94.
2. Gregory PD, Wegnar K, & Horz W. Histone acatylation and chromatin remodelling, Exp Cell Res. 2Ool; 285, 195-202.
3. Strahl BD, & AJlis CD. The language of covalent histone modifications. Nature 2000; 403: 41-45.
4. Roth SY, Denu JM & Allis CD. Hlatone acetyltransferases. Annu Rev Bibchem. 2001; 70: 81-120
5. Luger K, Mader AW, Richmond RK, et al. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 1997; 389: 251-60.
6. Davie JR. Covalent modifications of histones: expression from chromatin templates. Curr Opin Genet Dev 1998; 8: 173-8.
7. Gray GG, & Ekstrom TJ. The human histone deacetylase family. Exp Cell Res 2001; 262: 75-83.
8. Zhou X, Manks RA, Rifkind RA. et al. Cloning and characterization of a histone deacetytase, HDAC9, Proc Natl Acad Sci 2001; 19: 10572-7.
9. Landry J et al. The silencing protein SIR2 and its homoibgs are NAD-dependant protein deacetytases. Proc Natl Acad Sci 2000; 97: 5807-11.
10. Frye, R. A. Phyloganetic classification of prokaryotic and eukaryotic Sir2-1ike proteins. Biochem Biophys Res Commun 2000; 273: 793-8.
11. Grunstein M. Histone acetylation and chromatin structure and transcription. Nature 1997; 389: 349-52.
12. Kouzarides T. Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev 1999; 9: 40-8.
13. Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999; 98: 285-94.
14. Komberg RD. Chromatin structure: a repeating unit of histones and DNA.Science 1974; 184: 868-71.
15. Gu W, Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997; 90: 595-606.
16. Boyes J, Byfield P, Nakatani Y, et al. Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 1998; 396: 594-8.
17. Imhof A, Yang XJ, Ogryzko VV, et al.. Acetylation of general transcription factors by histone acetyltransferases. Curr Biol 1997; 7: 689-92.
18. Luo RX, Postigo AA. Dean DC. Rb interacts with histone deacetylase to repress transcription. Cell 1998; 92: 463-73.
19. Brehm A, Miska EA, McCance DJ, et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 1998; 391: 597-601.
20. Fuks F, Burgers WA, Godin N, et al.: Dnmt3a binds deacetyLases and is recruited by a sequence-specific repressor to silence transcription. Embo J 2001; 20: 2536-44.
21. Robertson KD, Alt-Si-Ali S, et al.: DNMTI forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 2000, 25: 338-342.
22. Jones PL, Veenstra G J, Wade PA, et al.: Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1998, 19: 187-191.
23. Johnson CA, Padget K, Austin CA, et al.: Deacetylase activity associates with topoisomerase II and is necessary for etoposide-induced apoptosis. J Biol Chem 2001; 276: 4539-42.
24. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell 1980, 20: 85-93.
25. Jenuwein T, AIlis CD. Translating the histone code. Science 2001; 293: 1074-1080.
26. Horlein A J, Naar AM, Heinzel T, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor.Nature 1995; 377: 397-404.
27. Chen JD, Evans RM: A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 1995; 377: 454-58.
28. Chen JD, Umesono K, Evans RM. SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers. Proc Natl Acad Sci 1996; 93: 7567-79.
29. Driscoll JE, Seachord CL, Lupisella JA, et al. Ligand-induced conformational changes in the human retinoic acid receptor detected using monoclonal antibodies. J Biol Chem 1996; 271: 22969-71
30. Heery DM, Kalkhoven E, Hoare S, et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 1997; 387: 733-38.
31. Jenster G, Spencer TE, Burcin MM, et al. Steroid receptor induction of gene transcription: A two-step model.Proc Natl Acad Sci USA 1997: 94: 7879-90.
32. Torchia J, Rose DW, Inostroza J, et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 1997; 387: 677-82.
33. He LZ, Guidez F, Tribioli C, et al. Distinct interactions of PML-RARalpha and PLZF-RARalpha with Co-repressors determine differential responses to RA in APL. Nat Genet 1998; 18: 126-35.
34. Grignani F, De Matteis S, Nervi C, et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 1998; 391: 815-8.
35. Lin RJ, Nagy L, Inoue S, et al. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 1998; 391: 811-4.
36. Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167-3215.
37. Guidez F, Ivins S, Zhu J, et al. Reduced retinoic acid-sensitivities of nuclearreceptor corepressorbinding to PML- and PLZF-RAR-alpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 1998; 91: 2634-40.
38. David G, Alland L, Hong SH, et al. Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 1998; 16: 2549-61.
39. Meyers S, Downing JR, Hiebert SW. Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: The runt homology domain is required for DNA binding and protein-protein interactions. Mol Cell Biol 1993; 13: 6336-51.
40. Hiebert SW, Downing JR, Lenny N, et al. Transcriptional regulation by the t(8;21) fusion protein, AML-1/ETO. Curr Top Microbiol Immunol 1996; 211: 253.
41. Kitabayashi I, Yokoyama A, Shimizu K, et al. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J 1998; 17: 2994-3007.
42. Frank R, Zhang J, Uchida H, et al. The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML 1B. Oncogene 1995; 11: 2667-78.
43. Wang JX, Hoshino T, Redner RL, et al. ETO, fusion partner in t(8-21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci 1998; 95: 10860-65.
44. Gelmetti V, Zhang JS, Fanelli M, et al. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol 1998; 18: 7185-92.
45. Downing JR, Look AT. MLL fusion genes in the 11q23 acute leukemias. Cancer Treat Res 1996; 84: 73-81.
46. Cimino G, Rapanotti MC, Sprovieri T, et al. ALL1 gene alterations in acute leukemia: Biological and clinical aspects. Haematologica 1998; 83: 350-57.
47. Janssen JW, Ludwig WD, Borkhardt A, et al. Pre-pre-B acute lymphoblastic leukemia: High frequency of alternatively spliced ALL 1-AF4 transcripts and absence of minimal residual disease during complete remission. Blood 1994; 84: 3835-43.
48. Sobulo OM, Borrow J, Tomek R, et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeioid leukemia with a t(11;16)(q23;p 13.3). Proc Natl Acad Sci USA1997; 94: 8732-37.
49. Rowley ID, Reshmi S, Sobulo O, et al. All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 1997; 90: 535-42.
50. Ida K, Kitabayashi I, Taki T, et al. Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood 1997; 90: 4699-706.
51. Borrow J, Stanton V Jr, Andresen JM, et al. The translocation t(8; 16)(p 11;p 13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 1996; 14: 33-39.
52. Carapeti M, Aguiar RC, Goldman JM, et al. A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood 1998; 91: 3127-34.
53. Chen L, Fischle W, Verdin E, et al. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 2001; 293: 1653-1657.
54. Dhordain P, Lin RI, Quief S, et al. The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. Nucleic Acids Res 1998; 26: 4645-51.
55. Ye BH. BCL-6 in the pathogenesis of non-Hodgkin's lymphoma. Cancer Invest 2000; 16: 356-365.
56. Melnick A, Carlile G, Ahmad KF, et al. Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Mol Cell Biol 2002; 22: 1804-1618.
57. Marks PA, Rifkind RA, Richon VM, et al. Histone deacetylase and cancer: causes and therapies. Nature 2001; 1: 194-202.
58. Carducci M, Bowling MK, Eisenberger M, et al. Phanylbutyrat e (PB) for refractory solid tumors: phase I clinical and pharmacologic evaluation of intravenous and oral PB. Anticancer Res. 1997; 17: 3972-3.
59. Yoshida M, Kijima M, Akita M, et al. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 1990; 265: 17174-9.
60. Kijima M, Yoshida M, Sugita K, et al. Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 1993; 268: 22429-35.
61. Newmark HL, Lupron JR, Young CW. Butyrate as a differentiating agent: pharmacokinetics, analogues and current status. Cancer Lett 1994; 78: 1-5.
62. Saito A, Yamashita T, Mariko Y, et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci U S A 1999; 96: 4592-7.
63. Nakajima H, Kim YB, Terano H, et al. FR90t228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 1998; 241: 126-33.
64. Kim YB, Lee KH, Sugita K, et al. Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene 1999; 18: 2461-70.
65. Finnin, M. S. et al. Structures of a histone deaostylase homologue bound to TSA and SAHA. Nature 1999; 401: 188-193.
66. Gottlicher M, Minucci S, Zhu P, et al.: Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. Embo I 2001; 20: 6969-78.
67. Phiel C J, Zhang F, Huang EY, et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvuleant, mood stabilizer, and teratogen. J BiolChem 2001; 276: 36734-41.
68. Kitamura K, Hoshi S, Koike M, et al.: Histone deacetyiase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid. Br J Haematol 2000; 108: 696-702.
69. Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167-215.
70. Candido EP, Reeves R, Davie JR. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 1978, 14: 105-113.
71. Marks PA, Richon VM, Breslow R, et al. Histone deacetylase inhibitore as new cancer drugs. Curr Opin Oncol 2001; 13: 477-83.
72. Ferrara FF, Fazi F, Bianchini A, et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 2001; 61: 2-7.
73. Wang J, Saunthararajah Y, Redner RL, et al.: Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res 1999, 59: 2766-69.
74. Murata M, Towatari M, Kosugi H, et al. Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228, on malignant lymphoid cells..Jpn J Cancer Res 2000; 91: 1154-1160.
75. Aron IL, Murphy T, Parthun MR, et al. The histone deacetylase inhibitor depsipeptide (FR901228) induces apoptosis via activation of the caspase 6 pathway concurrent with lysine specific acetylation in chronic lymphocytic leukemia cells. Blood 2001, 98: 807-808a.
76. Lavelle D, Chen YH, Hankewych M, et al. Histone deacetylase inhibitors increase p21 (WAF1) and induce apoptosis of human myeloma cell lines in dependent of decreased IL-6 receptor expression. Am. j Hematol 2001; 68: 170-176.
77. Richon VM, Sandhoff TW, Rifkind RA, et al. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 2000; 97: 10014-19.
78. Van Lint C, Emitiani S, Verdin E. The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr 1996; 5: 245-253.
79. Laribee RN, Klemsz MI. Loss of PU.1 expression following inhibition of histone deacetylases. J Immuno12001, 167: 5160-6.
80. Ruefli AA, Ausserlechner M J, Bernhard D, et al. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci U S A 2001; 98: 10633-6.
81. Sambucetti LC, Fischer DD, Zabludoff S, et al. Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects..I Biol Chem 1999; 274: 34940-7.
82. Richon VM, Sandhoff TW, Rifkind RA, et al. Histone deacetylase inhibitor selectively induces p21~(WAF1) expression and gene-associated Histone deacetylation. PNAS 2000; 97: 10014-9.
83. DiGiuseppe D, Weng LJ, Yu KH, et al. Phenylbutyrate-induced G1 arrest and apoptosis in myloid leukemia cells: structure-function analysis. Leukemia, 1999, 13: 1243-53.
84. Rosato RR, Almenara JA, Cartee L, et al. The cyclin-dependent kinase inhibitor flavopiridol disrupts sodium butyrate-induced p21WAF1/CIP1 expression and maturation while reciprocally potentiating apoptosis in human leukemia cells. Mol Cancer Ther 2002; 1: 252-66.
85. Sasakawa Y, Naoe Y, Inoue T, et al. Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem Pharmacol 2002; 64: 1079-90.
86. DeSchepper S, Bruwiere H, Verhulst T, et al. Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degredation of survivin. J Pharmacol Exp Ther 2003; 304: 881-8.
87. Almenara J, Rosato R, Grant S. synergistic induction of mitochondrial damage and apotosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 2002; 16: 1331-43.
88. Rahmani M, Dai Y, Grant S. The histone deacetylase inhibitor sodium butyrate interacts synergistically with phorbol myristate acetate (PMA) to induce mitochondrial damage and apotosis in human leukemia cells through a tumor necrosis factor-alpha-mediated process. Exp cell Res 2002; 277: 31-47.
89. Bernhard D, Skavortsov S, Tinhofer I, et al. Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts. Cell Death Differ 2001; 8: 1014-21.
90. Sawa H, Murakami H, Ohshima Y, et al. Histone histone deacetylase inhibitor sodium butyrate and trichostatin A induce apoptosis through an increase of the bcl-2-related protein Bad. Brain Tumor Pathol 2001; 18: 109-14.
91. Aron JL, Parthun MR, Marcucci G, et al. Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase-8-mediated apotosis and downregulation of c-FLIP protein. Blood 2003;
92. Butler LM, et al. Suderoylanilide hydroxamio acid, an inhibitor of histone descety[ase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res. 2000; 60: 5165-70.
93. Yosdida M. et al. Potent and specific inifbition of mammalian hlstone deenetylese both in vivo and in vitro by trichestatin A. J. Biof Chem 1990: 265, 17174-9.
94. Kim MS, et al. Histona deacetyieses induce angiogenas~ by negative regulation of tumor suppressor genes. Nature Mad, 2001; 7: 437-443.
95. Kwen HJ et al. HLstona deasetylese inhibitor FK228 inhibitshypoxia-inducad tumor angiogenasis. Nature Med.
96. He LZ, Tolentino T, Grayaon P, et al.: Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 2001, 108: 1321-30.
97. Warrell RP Jr, He LZ, Richon V, et al. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998; 90: 1621-5.
98. Novich S, Camacho L, Gallagher R, et al. Initial clinical evaluation of "transcription therapy" for cancer: all-trans retinoic acid plus phenylbutyrate. Blood 1999; 94: Suppl 1. p61a.
99. O'Connor OA, Kelly W, Wang ES, et al. Clinical development of the histone deacetylase inhibitor suberoylanalide hydroxamic acid (SAHA) in aggressive non-Hodgkin's lymphomas (NHL) and Hodgkin's disease. Blood 2001; 98: 611a.
1. Swirsky DM, Lian YS, Matthews JG, et al. 8:21 translocation in acute granulocytic leukaemia: cytological, cytochemical and clinical features. British Journal of Haematology 1984; 56: 199-213.
2. Ferrara F, Vecchio LD. Acute myloid leukemia with t(8;21)/AML/ETO: a distinct biological and clinical entity. Haematologica 2002; 87: 306-19.
3. Erickson P, Gao J, Chang KS, Look T, et al. Identification of breakpoints in t(8:21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood 1992; 80: 1825-31.
4. Miyoshi H, Kozu T, Shimizu K, et al. 1993 The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO Journal 12, 2715-21.
5. Ogawa E, Maruyama M, Kagoshima H, et al. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. proceedings of tile, National Academy of Sciences of the United States of America, 1993; 90: 6859-63.
6. Levanon D, Negreanu V, Bernstein Y, et al. AML1, AML2, and AML3, the human members of the runt domain gene family: cDNA structure, expression, and chromosomal localization. Genomics 1994; 23: 425-32.
7. Corsetti MT & Calabi F. Lineage- and stage-specific expression of runt box polypeptides in primitive and definitive hematopoiesis. Blood, 1997; 89: 2359-68.
8. Golling G, Li L, Pepling M, et al. Drosophila homologs of the proto-oncogene product PEBP2/CBF bela regulate the DNA-binding properties of Runt. Molecular and Celhdar Biology 1996; 16: 932-42.
9. Friedman AD. Leukemogenesis by CBF oncoproteins. Leukemia1999; 13: 1932-42.
10. Kania MA, Bonner AS, Duffy JB, et al. The drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in developing nervous system. Genes Dev 1990; 4: 1701-13.
11. Meyers S, Downing JR, Hiebert SW. Identification of AML land the t(8;21) translocation protein AML1-eto as sequence specific DNA binding proteins: the runt domain is required for DNA binding and protein-protein interactions. Mol Cell Biol 1993; 13: 6336-45.
12. Lutterbach B, Hiebert SW. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene 2000; 245: 223-35.
13. Speck NA, Stacy T, Wang Q, et al. Core-binding factor: a central player in hematopoiesis and leukemia. Cancer Res 1999; 59: 1789-93.
14. Uchida H, Zhang J, Nimer SD. AML1A and AML1B can transactivate the human IL-3 promoter. J Immunol 1997; 158: 2251-8.
15. Prosser H.M, WottonD, Gegonne A., et al. A phorbol ester response element within the human T-cell receptor O-chain enhancer. Proceedings of the National Academy of Sciences of the United States of America 1992; 89: 9934-38.
16. Takahashi A, Satake M, Yamaguchi-Iwai Y, et al. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood 1995; 86: 607-16.
17. Wotton D, Ghysdael J, Wang S,et al. Cooperative binding of Ets-1 and core binding factor to DNA.Molecular and Cellular Biology 1994; 14, 840-50.
18. Zhang DE, Hohaus S, Voso MT, et al. (b) Function of PU. 1 (Spi-1), C/EBP, and AML1 in early myelopoiesis: regulation of multiple myeloid CSF receptor promoters. Current Topics in Microbiology and Immunology 1996211, 137-47.
19. Lutterbach B, Westendorf JJ, Linggi B, et al. A mechanism oftranscriptional repression by AML1, the target of multiple chromosome translocations in leukemia. J Biol Chem 2000; 275: 651-6.
20. Britos-Bray, M. & Friedman, A.D. Core binding factor cannot synergistically activate the myeloperoxidase proximal enhancer in immature myeloid cells without c-Myb. Molecular and Cellular Biology 1997; 17: 5127-35.
21. Petrovick MS, Hiebert SW, Friedman AD, et al. Multiple functional domains of AMLI: PU. 1 and C/EBPa synergize with different regions of AML1. Mol Cellular Bio 1998; 18: 3915-25.
22. Kitabayashi I, Yokoyama A, Shimizu K, et al. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO 1998; 17: 2994-3004.
23. Chen H, Lin RJ, Schlitz RL, et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 1997; 90: 569-80.
24. Gu W, & Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997; 90: 595-606.
25. Zhang DE, Hetherington CJ, Meyers S, et al. CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Molecular and Cellular Biology 1996; 16: 1231-40.
26. Zhang YW, Bae SC, Huang G, et al. A novel transcript encoding an N-terminally truncated AML1/PEBP2 alphaB protein interferes with transactivation and blocks granulocytic differentiation of 32Dc13 myeloid cells. Molecular and Cellular Biology 1997; 17: 4133-45.
27. Wang Q, Stacy T, Binder M, et al. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Pro Nati Aca Sci USA 1996; 93: 3444-9.
28. Wang Q, Stacy T, Miller JD, et al. The CBFbeta subunit is essential forCBFalpha2 (AML1) function in vivo. Cell 199687, 697-708.
29. Okada T, van Deursen J, Hiebert SW, et al. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell, 1996; 84: 321-30.
30. Roumier C, Fenaux P, Lafage M, et al. New mechanisms of AML1 gene alteration in hematological malignancies.Leukemia. 2003; 17: 9-16.
31. Okuda T, Cai Z, Yang S et al. Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 1998; 91: 3134-43.
32. Mukouyama Y, Chiba N, Hara T, The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad-mesonephros region. Dev Biol 2000; 220: 27-36
33. Wolford JK, Prochazka M. Structure and expression of the human MTG8/ETO gene. Gene 1998; 212: 103-9
34. Feinstein EG, Kornfield K, Hogness DS, et al. Identification of homeotic target genes in Drosophila melanogaster including nervg a proto-oncogene homologue. Genetics 1995; 140: 573-86.
35. Kitabayashi I, Ida K, Morohoshi E, et al. The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR 1. Mol Cell Biol 1998; 18: 846-58.
36. Era T, Asou N, Kunisada T, et al. Identification of two transcripts of AML1/EYO-fused gene in t(8;21) leukemic cells and expression of wild-type ETO gene in hematopoietic cells. Genes, Chromo Cancer, 199513, 25-33.
37. Wang J, Hoshino T, Redner RL, et al. ETO, fusion partner in t(8:21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC 1 complex. Pro Nati Aca Sci USA 1998; 95: 10860-65.
38. Lutterbach B, Westendorf JJ, Linggi B, et al. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol 1998; 18: 7176-84.
39. Zhang J, Hug BA, Huang EY, et al. Oligomerization of ETO is obligatory for corepressor interaction Mol Cell Biol 2001; 21: 156-63.
40. Hildebrand D, Tiefenbach J, Heinzel T, et al. Multiple regions of ETO cooperate in transcriptional repression. J Biol Chem 2001; 276: 9889-95.
41. Meyers S, Lenny N, & Hiebert SW. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol. 1995; 15: 1974-1982.
42. Frank R, Zhang J, Uchida H, The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AMLIB. Onco Gene 1995; 11: 2667-74.
43. Hug BA, Lee SY, Kinsler EL, Cooperative function of AML1-ETO corepressor recruitment domains in the expansion of primary bone marrow cells. Cancer Res. 2002 May 15; 62(10): 2906-12.
44. Da Silva N, Meyer-Monard S, Menot ML, Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO. Hematol J. 2000; 1(5): 316-28.
45. Mulloy JC, Cammenga J, MacKenzie KL, The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood. 2002; 99: 15-23.
46. Lutterbach B, Sun D, Schuetz J et al. The MYND motif is required for repression of basal transcription from the multidrug resistance 1 promoter by the t(8;21) fusion protein. Mol Cell Biol 1998; 18: 3604-11.
47. Schwieger M, Lohler J, Friel J, AML1-ETO inhibits maturation of multiple lymphohematopoietic lineages and induces myeloblast transformation in synergy with ICSBP deficiency. J Exp Med. 2002; 196: 1227-40.
48. Vangala RK, Heiss-Neumann MS, Rangatia JS, The myeloid master regulator transcription factor PU. 1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood. 2003; 101: 270-7.
49. Tanaka K, Tanaka T, Kurokawa M, et al. The AML1/ETO(MTGS) and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2beta(CBFbeta) in the nucleus more efficiently than wild-type AML1. Blood 1998; 91: 1688-99.
50. Chen LE, lto K, Murakami y, et al. The capacity of polyomavirus enhancer binding protein 2aB (AML1/Cbfa2) to stimulate polyomavirus DNA replication is related to its affinity for the nuclear matrix. Mol Cell Biol 1998; 18: 4165-76.
51. Banker DE, Radich J, Becker A, et al. The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults. Clin Cancer Res 1998; 4: 3051-62.
52. Yergeau DA, Hetherington CJ, Wang Q, et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nature Gene1997; 15: 303-6.
53. Westendorf JJ, Yamamoto CM, Lenny N, et al. The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Mol Cell Biol 1998; 18: 322-33.
54. Wang J, Wang M & Liu JM. Transformation properties of the ETO gene, fusion partner in t(8;21) leukemias. Cancer Res 1997; 57: 2951-55.
55. Barseguian K, Lutterbach B, Hiebert SW, et al. Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins. Pro Nati Aca Sci USA 2002; 99: 15434-39.
56. Miyamoto T, Weissman IL, Akashi K. et al. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation.Proc Natl Acad Sci U S A. 2000 Jun 20; 97(13): 7521-6.
57. Burel SA, Harakawa N, Zhou L, et al. Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation. Mol Cell Biol 2002; 21: 5577-90.
58. Asou H, Tashiro S, Hamamoto K, et al. Establishment of a human acute myeloid leukemia cell line (Kasumi-1) with 8;21 chromosome translocation. Blood 1991 May 1; 77(9): 2031-6
59. Matozaki S, Nakagawa T, Kawaguchi R, et al. Establishment of a myeloid leukaemic cell line (SKNO-1) from a patient with t(8;21) who acquired monosomy 17 during disease progression. Br J Haematol 1995 Apr; 89(4): 805-11.
60. Melnick A, Carlile GW, McConnell MJ, AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein. Blood 2000; 96: 3939-47
61. Kurokawa M, Tanaka T, Tanaka K, et al. Overexpression of the AML1 proto-oncoprotein in NIH3T3 cells leads to neoplastic transformation depending on the DNA-binding and transactivational potencies. Oncogene 1996; 12: 883-92.
62. Namba K, Abe M, Saito S, et al. Indispensable role of the transcription factor PEBP2/CBF in angiogenic activity of a murine endothelial cell MSS31. Oncogene 2000; 19: 106-14.
63. Hwang ES, Hong JH, Bae SC, et al. Regulation of c-fos gene transcription and myeloid cell differentiation by acute myeloid leukemia 1 and acute myeloid leukemia-MTG8, a chimeric leukemogenic derivative of acute myeloid leukemia 1. FEBS Lett 1999 Mar 5; 446(1): 86-90
64. Strom DK, Nip J, et al. Westendorf JJ, et al. Expression of the AML-1 oncogene shortens the G(1) phase of the cell cycle. J Biol Chem 2000; 275: 3438-45
65. Rahoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role ofAML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood 2000; 96: 2108-15.
66. Yuan Y, Zhou L, Miyamoto T, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci U S A. 2001; 98: 10398-403.
67. DeGuzman CG, Warren AJ, Zhang Z, Hematopoietic stem cell expansion and distinct myeloid developmental abnormalities in a murine model of the AML1-ETO translocation. Mol Cell Biol. 2002 Aug; 22(15): 5506-17.
68. Higuchi M, O'Brien D, Kumaravelu P, Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia.Cancer Cell. 2002 Feb; 1(1): 63-74.
69. Pabst T, Mueller BU, Harakawa N, et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001 Apr; 7(4): 444-51.
70. Rhoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood. 2000 Sep 15; 96(6): 2108-15.
2. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukemia. Nature 1998; 391: 815-8.
3. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukemia. Nature 1998; 391: 811-4.
4. Yoshida M, Kijima M, Akita M, Beppu T. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 1990; 265: 17174-9.
5. Newmark HL, Lupton JR, Young CW. Butyrate as a differentiating agent: pharmacokinetics, analogues and current status. Cancer Lett 1994; 78: 1-5.
6. Carducci M, Bowling MK, Eisenberger M, Sinibaldi V, Chen T, Nor D, et al. Phenylbutyrate (PB) for refractory solid tumors: phase I clinical and pharmacologic evaluation of intravenous and oral PB. Anticancer Res 1997; 17: 3972-3.
7. Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci U S A 1998; 95: 10860-5.
8. Wang L, Hiebert SW. TEL contacts multiple co-repressors and specifically associates with histone deacetylase-3. Oncogene 2001; 20: 3716-25.
9. Kass SD, Pruss D, and Wolffe AP. How dose NDA methylation repress transcription?Trends Genet 1997; 13: 444-9.
10. Pinto A, Attadia VV, Fusco LA, et al. 5-Aza-2'-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemia. Blood 1984; 64: 922-9.
11. Momparler RL, Dore BT, Momparler LF, et al. Effect of 5-Aza-2'-deoxycytidine and retinoic acid on differentiation and c-myc expression in HL-60 myeloid leukemic cells. Cancer Lett 1990; 54: 21-8.
12. Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MeCP2 involves a histone deacetylase to reprss transcroption. Nat Genet 1998; 19: 187-91.
13. Nan X, Ng HH, Johnson CA, et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393: 386-9.
14. Weidner N, Semple JP, Welch WR, et al. Tumor angioangesis and metastasis-correlation in invasive breast carcinoma. N Engl J Med 1991; 324: 1-8.
15. Davie JR. Covalent modifications of histones: expression from chromatin templates. Curr Opin Genet Dev 1998; 8: 173-8.
16. Kouzarides T. Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev 1999; 9: 40-8.
17. Redner RL, Wang J, Liu JM. Chromatin remodeling and leukemia: new therapeutic paradigms. Blood 1999; 94: 417-428.
18. Warrell RP Jr, He LZ, Richon V, et al. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998; 90: 1621-5.
19. Ferrara F, Vecchio LD. Acute myeloid leukemia with t(8;21)/AML1/ETO: a distinct biological and clinical entity. Haematologica 2002; 87: 306-19.
20. Lutterbach B, Hiebert SW. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene 2000; 245: 223-35.
21. Speck NA, Stacy T, Wang Q, et al. Core-binding factor: a central player in hematopoiesis and leukemia. Cancer Res 1999; 59: 1789-93.
22. Uchida H, Zhang J, Nimer SD. AML1A and AML1B can transactivate the human IL-3 promoter. J Immunol 1997; 158: 2251-8.
23. Prosser H.M, WottonD, Gegonne A., et al. A phorbol ester response element within the human T-cell receptor O-chain enhancer. Proceedings of the National Academy of Sciences of the United States of America 1992; 89: 9934-38.
24. Takahashi A, Satake M, Yamaguchi-Iwai Y, et al. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood1995; 86: 607-16.
25. Wotton D, Ghysdael J, Wang S,et al. Cooperative binding of Ets-1 and core binding factor to DNA.Molecular and Cellular Biology 1994; 14, 840-50.
26. Zhang DE, Hohaus S, Voso MT, et al. (b) Function of PU. 1(Spi- 1), C/EBP, and AML1 in early myelopoiesis: regulation of multiple myeloid CSF receptor promoters. Current Topics in Microbiology and Immunology 1996211, 137-47.
27. Lutterbach B, Westendorf JJ, Linggi B, et al. A mechanism of transcriptional repression by AML1, the target of multiple chromosome translocations in leukemia. J Biol Chem 2000; 275: 651-6.
28. Lutterbach B, Westendorf JJ, Linggi B, et al. () ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Molecular and Cellular Biology, 1998; 18: 7176-84.
29. Wang J, Wang M. & Liu J.M. Transformation properties of the ETO gene, fusion partner in t(8;21) leukemias. Cancer Rese 1997; 57: 2951-5.
30. Gelmetti V, Zhang J, Fanelli M., et al. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Molecular and Cellular Biology, 1998; 18: 7185-91.
31. Baylin SB, Herman JG. DNA hypermethylation in tumorigenesis. Trends Genet 2000; 16: 168-74.
32. Momparler RL, Bovenzi V. DNA methylation and cancer. J Cell Physiol 2000; 183: 145-54.
33. Rivard GE, Momparler RL, Demers J, et al. Phase I study on 5-aza-2'-deoxycytidine in children with acute leukemia. Leuk Res 1981; 5: 453-62.
34. Cameron EE, Kurtis E, Myohanen BS, et al. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 1999; 21: 103-7.
35. Asou H, Tashiro S, Hamamoto K, et al. Establishment of a human acute myeloid leukemia cell line (Kasumi-1) with 8;21 chromosome translocation. Blood 1991; 77: 2031-6.
36. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors:inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst,2000, 92: 1210-1216.
37. Mulloy JC, Cammenga J, Mackenzie KL, et al. The AML1-ETOfusion protein promotes the expansion of human hematopoietic ceils. Blood 2002; 99: 15-23.
38. Kurokawa M, Tanaka T, Tanaka K, et al. Overexpression of the AML1 protooncoprotein in NIH3T3 cells leads to neoplastic transformation depending on the DNA-binding and transactivational potencies. Oncogene 1996; 12: 883-92.
39. Westendorf JJ, Yamamoto CM, Lenny N, et al. The t(8;21) fusion product, AML1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Molecular and Cellular Biology. 1998; 18: 322-33.
40. Sakakura C, Yamaguchi-Iwai Y, Satake M, et al. Growth inhibition and induction of differentiation of t(8;21) acute myeloid leukemia cells by the DNA-binding domain of PEBP2 and the AML1/MTG8(ETO)-specific antisence loigonucleotide. Proc. Natl. Acad. Sci. 1994; 91: 11723-7.
41. Rhoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood 2000; 96: 2108-15.
42. Wang JX, Saunthararajah Y, Redne RL, et al. Inhitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res, 1999, 59: 2766-2769.
43. Gore SD, Samid D, Weng LJ. Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on primary neoplastic myeloid cells. Clin Cancer Res. 1997, 3: 1755-1762.
44. Van Lint C, Emiliani S, Verdin E. The expression of a small fraction of cellular gene is changed in response to histone hyperacetylation. Gene Expr. 1996; 5: 245-4.
45. Klisvic MI, Maghraby EA, Parthun MR, et al. Depsipeptide (FR901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1-ETO-positive leukemic cells. Leukemia 2003; 17: 350-8.
46. Da Silva N, Meyer-Monard S, Menot ML, Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO. Hematol J. 2000; 1(5): 316-28.
47. Almenara J, Rosato R, Grant S. synergistic induction of mitochondrial damage and apotosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 2002; 16: 1331-43.
48. Rahmani M, Dai Y, Grant S. The histone deacetylase inhibitor sodium butyrate interacts synergistically with phorbol myristate acetate (PMA) to induce mitochondrial damage and apotosis in human leukemia cells through a tumor necrosis factor-alpha-mediated process. Exp cell Res 2002; 277: 31-47.
49. Bernhard D, Skavortsov S, Tinhofer I, et al. Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts. Cell Death Differ 2001; 8: 1014-21.
50. Sawa H, Murakami H, Ohshima Y, et al. Histone histone deacetylase inhibitor sodium butyrate and trichostatin A induce apoptosis through an increase of the bc1-2-related protein Bad. Brain Tumor Pathol 2001; 18: 109-14.
51. Aron JL, Parthun MR, Marcucci G, et al. Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase-8-mediated apotosis and downregulation of c-FLIP protein. Blood 2003;
52. Ferreira R, Naguibneva I, Mathieu M, et al. Cell cycle-dependent recruitment of HDAC-1 correlates with deacetylation of histone H4 on an Rb-E2F target promoter. EMBO 2001; 9: 794-9.
53. Brehm A, Miska EA, McCance DJ, et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 1998; 391: 597-601.
54. Brehm A, Miska EA, Reid J, et al. The cell cycle-regulating transcription factors E2F-RB. Br J Cancer suppl 1 1999; 80: 38-41.
55. Richon VM, Sandhoff TW, Rifkind RA, et al. Histone deacetylase inhibitor selectively induces p21~(WAF1) expression and gene-associated Histonedeacetylation. PNAS 2000; 97: 10014-9.
56. DiGiuseppe D, Weng LJ, Yu KH, et al. Phenylbutyrate-induced G1 arrest and apoptosis in myloid leukemia cells: structure-function analysis. Leukemia, 1999, 13: 1243-53.
57. Sowa Y. Sakai T. Butyrate as a model for "gene-regulating chemoprevention and chemotherapy". Biofactors 2000; 12: 283-7.
58. Rosato RR, Almenara JA, Cartee L, et al. The cyclin-dependent kinase inhibitor flavopiridol disrupts sodium butyrate-induced p21WAF1/CIP1 expression and maturation while reciprocally potentiating apoptosis in human leukemia cells. Mol Cancer Ther 2002; 1: 252-66.
59. Sasakawa Y, Naoe Y, Inoue T, et al. Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem Pharmacol 2002; 64: 1079-90.
60. DeSchepper S, Bruwiere H, Verhulst T, et al. Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degredation of survivin. J Pharmacol Exp Ther 2003; 304: 881-8.
61. Lavelle D, Chen YH, Hankewych M, et al. Histone deacetylase inhibitors increase p21WAF1 and induce apoptosis of human myeloma cell lines independent of decreased IL-6 receptor expression. Am J Hematol, 2001; 68: 170-8.
62. Pili R, Kruszewski MP, Hager BW, et al. Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis. Cancer Reser 2001; 61: 1477-85.
63. Kim MS et al. Histona deacetyieses induce angiogenesis by negative regulation of tumor suppressor genes. Nature Mad, 2001; 7: 437-43.
64. Kwen HJ et al. HLstona deasetylese inhibitor FK228 inhibits hypoxia-inducad tumor angiogenasis. Nature Med.(in the press).
65. Gore SD, Miller CB, Weng LJ, et al. Improved hematopoiesis in patients with myelodysplasetic syndromes (MDS) and acute myeloid leukemia (AML) following administration of the putative differentiating agent sodium phenylbutyrate (SPB). Blood 1996; 88(suppll)582a.
66. Niitsu N, Hayashi Y, Sugita K, et al. Sensitization by 5-Aza-2'-deoxycytidine of leukemia cells with MLL abnormalities toinduction of differentiation by all-trans retinoic acid and 1α,25-dihydroxyvitamin D3. British J Haematol 2001; 112: 315-26.
67. Eden S, hashimshony T, Keshet I, et al. DNA methylation models histone acetylation. Nature 1998; 394-42.
68. Zou WG, Lakshmanan RR, Beal MD, et al. DNA methyltransferase inhibition enhances apoptosis induced by histone deacetylase inhibitors. Cancer Resear 2001; 61: 1327-33.
69. Shaker S, Bernstein M, Momparler LF, et al. Preclinical evaluation of antineoplastic activity of inhitors of DNA methylation (5-Aza-2'-deoxycytidine) and histone deacetylation (trichostatin A, depsipeptide) in combination against myeloid leukemia cells. Leukemia Research 2003; 27: 437-44.
1. Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999; 98: 285-94.
2. Gregory PD, Wegnar K, & Horz W. Histone acatylation and chromatin remodelling, Exp Cell Res. 2Ool; 285, 195-202.
3. Strahl BD, & AJlis CD. The language of covalent histone modifications. Nature 2000; 403: 41-45.
4. Roth SY, Denu JM & Allis CD. Hlatone acetyltransferases. Annu Rev Bibchem. 2001; 70: 81-120
5. Luger K, Mader AW, Richmond RK, et al. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 1997; 389: 251-60.
6. Davie JR. Covalent modifications of histones: expression from chromatin templates. Curr Opin Genet Dev 1998; 8: 173-8.
7. Gray GG, & Ekstrom TJ. The human histone deacetylase family. Exp Cell Res 2001; 262: 75-83.
8. Zhou X, Manks RA, Rifkind RA. et al. Cloning and characterization of a histone deacetytase, HDAC9, Proc Natl Acad Sci 2001; 19: 10572-7.
9. Landry J et al. The silencing protein SIR2 and its homoibgs are NAD-dependant protein deacetytases. Proc Natl Acad Sci 2000; 97: 5807-11.
10. Frye, R. A. Phyloganetic classification of prokaryotic and eukaryotic Sir2-1ike proteins. Biochem Biophys Res Commun 2000; 273: 793-8.
11. Grunstein M. Histone acetylation and chromatin structure and transcription. Nature 1997; 389: 349-52.
12. Kouzarides T. Histone acetylases and deacetylases in cell proliferation. Curr Opin Genet Dev 1999; 9: 40-8.
13. Kornberg RD, Lorch Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 1999; 98: 285-94.
14. Komberg RD. Chromatin structure: a repeating unit of histones and DNA.Science 1974; 184: 868-71.
15. Gu W, Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997; 90: 595-606.
16. Boyes J, Byfield P, Nakatani Y, et al. Regulation of activity of the transcription factor GATA-1 by acetylation. Nature 1998; 396: 594-8.
17. Imhof A, Yang XJ, Ogryzko VV, et al.. Acetylation of general transcription factors by histone acetyltransferases. Curr Biol 1997; 7: 689-92.
18. Luo RX, Postigo AA. Dean DC. Rb interacts with histone deacetylase to repress transcription. Cell 1998; 92: 463-73.
19. Brehm A, Miska EA, McCance DJ, et al. Retinoblastoma protein recruits histone deacetylase to repress transcription. Nature 1998; 391: 597-601.
20. Fuks F, Burgers WA, Godin N, et al.: Dnmt3a binds deacetyLases and is recruited by a sequence-specific repressor to silence transcription. Embo J 2001; 20: 2536-44.
21. Robertson KD, Alt-Si-Ali S, et al.: DNMTI forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 2000, 25: 338-342.
22. Jones PL, Veenstra G J, Wade PA, et al.: Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 1998, 19: 187-191.
23. Johnson CA, Padget K, Austin CA, et al.: Deacetylase activity associates with topoisomerase II and is necessary for etoposide-induced apoptosis. J Biol Chem 2001; 276: 4539-42.
24. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell 1980, 20: 85-93.
25. Jenuwein T, AIlis CD. Translating the histone code. Science 2001; 293: 1074-1080.
26. Horlein A J, Naar AM, Heinzel T, et al. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor.Nature 1995; 377: 397-404.
27. Chen JD, Evans RM: A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 1995; 377: 454-58.
28. Chen JD, Umesono K, Evans RM. SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers. Proc Natl Acad Sci 1996; 93: 7567-79.
29. Driscoll JE, Seachord CL, Lupisella JA, et al. Ligand-induced conformational changes in the human retinoic acid receptor detected using monoclonal antibodies. J Biol Chem 1996; 271: 22969-71
30. Heery DM, Kalkhoven E, Hoare S, et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 1997; 387: 733-38.
31. Jenster G, Spencer TE, Burcin MM, et al. Steroid receptor induction of gene transcription: A two-step model.Proc Natl Acad Sci USA 1997: 94: 7879-90.
32. Torchia J, Rose DW, Inostroza J, et al. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 1997; 387: 677-82.
33. He LZ, Guidez F, Tribioli C, et al. Distinct interactions of PML-RARalpha and PLZF-RARalpha with Co-repressors determine differential responses to RA in APL. Nat Genet 1998; 18: 126-35.
34. Grignani F, De Matteis S, Nervi C, et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 1998; 391: 815-8.
35. Lin RJ, Nagy L, Inoue S, et al. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 1998; 391: 811-4.
36. Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167-3215.
37. Guidez F, Ivins S, Zhu J, et al. Reduced retinoic acid-sensitivities of nuclearreceptor corepressorbinding to PML- and PLZF-RAR-alpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 1998; 91: 2634-40.
38. David G, Alland L, Hong SH, et al. Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 1998; 16: 2549-61.
39. Meyers S, Downing JR, Hiebert SW. Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: The runt homology domain is required for DNA binding and protein-protein interactions. Mol Cell Biol 1993; 13: 6336-51.
40. Hiebert SW, Downing JR, Lenny N, et al. Transcriptional regulation by the t(8;21) fusion protein, AML-1/ETO. Curr Top Microbiol Immunol 1996; 211: 253.
41. Kitabayashi I, Yokoyama A, Shimizu K, et al. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J 1998; 17: 2994-3007.
42. Frank R, Zhang J, Uchida H, et al. The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML 1B. Oncogene 1995; 11: 2667-78.
43. Wang JX, Hoshino T, Redner RL, et al. ETO, fusion partner in t(8-21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci 1998; 95: 10860-65.
44. Gelmetti V, Zhang JS, Fanelli M, et al. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol 1998; 18: 7185-92.
45. Downing JR, Look AT. MLL fusion genes in the 11q23 acute leukemias. Cancer Treat Res 1996; 84: 73-81.
46. Cimino G, Rapanotti MC, Sprovieri T, et al. ALL1 gene alterations in acute leukemia: Biological and clinical aspects. Haematologica 1998; 83: 350-57.
47. Janssen JW, Ludwig WD, Borkhardt A, et al. Pre-pre-B acute lymphoblastic leukemia: High frequency of alternatively spliced ALL 1-AF4 transcripts and absence of minimal residual disease during complete remission. Blood 1994; 84: 3835-43.
48. Sobulo OM, Borrow J, Tomek R, et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeioid leukemia with a t(11;16)(q23;p 13.3). Proc Natl Acad Sci USA1997; 94: 8732-37.
49. Rowley ID, Reshmi S, Sobulo O, et al. All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 1997; 90: 535-42.
50. Ida K, Kitabayashi I, Taki T, et al. Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood 1997; 90: 4699-706.
51. Borrow J, Stanton V Jr, Andresen JM, et al. The translocation t(8; 16)(p 11;p 13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 1996; 14: 33-39.
52. Carapeti M, Aguiar RC, Goldman JM, et al. A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood 1998; 91: 3127-34.
53. Chen L, Fischle W, Verdin E, et al. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 2001; 293: 1653-1657.
54. Dhordain P, Lin RI, Quief S, et al. The LAZ3(BCL-6) oncoprotein recruits a SMRT/mSIN3A/histone deacetylase containing complex to mediate transcriptional repression. Nucleic Acids Res 1998; 26: 4645-51.
55. Ye BH. BCL-6 in the pathogenesis of non-Hodgkin's lymphoma. Cancer Invest 2000; 16: 356-365.
56. Melnick A, Carlile G, Ahmad KF, et al. Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Mol Cell Biol 2002; 22: 1804-1618.
57. Marks PA, Rifkind RA, Richon VM, et al. Histone deacetylase and cancer: causes and therapies. Nature 2001; 1: 194-202.
58. Carducci M, Bowling MK, Eisenberger M, et al. Phanylbutyrat e (PB) for refractory solid tumors: phase I clinical and pharmacologic evaluation of intravenous and oral PB. Anticancer Res. 1997; 17: 3972-3.
59. Yoshida M, Kijima M, Akita M, et al. Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 1990; 265: 17174-9.
60. Kijima M, Yoshida M, Sugita K, et al. Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 1993; 268: 22429-35.
61. Newmark HL, Lupron JR, Young CW. Butyrate as a differentiating agent: pharmacokinetics, analogues and current status. Cancer Lett 1994; 78: 1-5.
62. Saito A, Yamashita T, Mariko Y, et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci U S A 1999; 96: 4592-7.
63. Nakajima H, Kim YB, Terano H, et al. FR90t228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 1998; 241: 126-33.
64. Kim YB, Lee KH, Sugita K, et al. Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene 1999; 18: 2461-70.
65. Finnin, M. S. et al. Structures of a histone deaostylase homologue bound to TSA and SAHA. Nature 1999; 401: 188-193.
66. Gottlicher M, Minucci S, Zhu P, et al.: Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. Embo I 2001; 20: 6969-78.
67. Phiel C J, Zhang F, Huang EY, et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvuleant, mood stabilizer, and teratogen. J BiolChem 2001; 276: 36734-41.
68. Kitamura K, Hoshi S, Koike M, et al.: Histone deacetyiase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid. Br J Haematol 2000; 108: 696-702.
69. Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167-215.
70. Candido EP, Reeves R, Davie JR. Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 1978, 14: 105-113.
71. Marks PA, Richon VM, Breslow R, et al. Histone deacetylase inhibitore as new cancer drugs. Curr Opin Oncol 2001; 13: 477-83.
72. Ferrara FF, Fazi F, Bianchini A, et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 2001; 61: 2-7.
73. Wang J, Saunthararajah Y, Redner RL, et al.: Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res 1999, 59: 2766-69.
74. Murata M, Towatari M, Kosugi H, et al. Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228, on malignant lymphoid cells..Jpn J Cancer Res 2000; 91: 1154-1160.
75. Aron IL, Murphy T, Parthun MR, et al. The histone deacetylase inhibitor depsipeptide (FR901228) induces apoptosis via activation of the caspase 6 pathway concurrent with lysine specific acetylation in chronic lymphocytic leukemia cells. Blood 2001, 98: 807-808a.
76. Lavelle D, Chen YH, Hankewych M, et al. Histone deacetylase inhibitors increase p21 (WAF1) and induce apoptosis of human myeloma cell lines in dependent of decreased IL-6 receptor expression. Am. j Hematol 2001; 68: 170-176.
77. Richon VM, Sandhoff TW, Rifkind RA, et al. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A 2000; 97: 10014-19.
78. Van Lint C, Emitiani S, Verdin E. The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr 1996; 5: 245-253.
79. Laribee RN, Klemsz MI. Loss of PU.1 expression following inhibition of histone deacetylases. J Immuno12001, 167: 5160-6.
80. Ruefli AA, Ausserlechner M J, Bernhard D, et al. The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species. Proc Natl Acad Sci U S A 2001; 98: 10633-6.
81. Sambucetti LC, Fischer DD, Zabludoff S, et al. Histone deacetylase inhibition selectively alters the activity and expression of cell cycle proteins leading to specific chromatin acetylation and antiproliferative effects..I Biol Chem 1999; 274: 34940-7.
82. Richon VM, Sandhoff TW, Rifkind RA, et al. Histone deacetylase inhibitor selectively induces p21~(WAF1) expression and gene-associated Histone deacetylation. PNAS 2000; 97: 10014-9.
83. DiGiuseppe D, Weng LJ, Yu KH, et al. Phenylbutyrate-induced G1 arrest and apoptosis in myloid leukemia cells: structure-function analysis. Leukemia, 1999, 13: 1243-53.
84. Rosato RR, Almenara JA, Cartee L, et al. The cyclin-dependent kinase inhibitor flavopiridol disrupts sodium butyrate-induced p21WAF1/CIP1 expression and maturation while reciprocally potentiating apoptosis in human leukemia cells. Mol Cancer Ther 2002; 1: 252-66.
85. Sasakawa Y, Naoe Y, Inoue T, et al. Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem Pharmacol 2002; 64: 1079-90.
86. DeSchepper S, Bruwiere H, Verhulst T, et al. Inhibition of histone deacetylases by chlamydocin induces apoptosis and proteasome-mediated degredation of survivin. J Pharmacol Exp Ther 2003; 304: 881-8.
87. Almenara J, Rosato R, Grant S. synergistic induction of mitochondrial damage and apotosis in human leukemia cells by flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). Leukemia 2002; 16: 1331-43.
88. Rahmani M, Dai Y, Grant S. The histone deacetylase inhibitor sodium butyrate interacts synergistically with phorbol myristate acetate (PMA) to induce mitochondrial damage and apotosis in human leukemia cells through a tumor necrosis factor-alpha-mediated process. Exp cell Res 2002; 277: 31-47.
89. Bernhard D, Skavortsov S, Tinhofer I, et al. Inhibition of histone deacetylase activity enhances Fas receptor-mediated apoptosis in leukemic lymphoblasts. Cell Death Differ 2001; 8: 1014-21.
90. Sawa H, Murakami H, Ohshima Y, et al. Histone histone deacetylase inhibitor sodium butyrate and trichostatin A induce apoptosis through an increase of the bcl-2-related protein Bad. Brain Tumor Pathol 2001; 18: 109-14.
91. Aron JL, Parthun MR, Marcucci G, et al. Depsipeptide (FR901228) induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase-8-mediated apotosis and downregulation of c-FLIP protein. Blood 2003;
92. Butler LM, et al. Suderoylanilide hydroxamio acid, an inhibitor of histone descety[ase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res. 2000; 60: 5165-70.
93. Yosdida M. et al. Potent and specific inifbition of mammalian hlstone deenetylese both in vivo and in vitro by trichestatin A. J. Biof Chem 1990: 265, 17174-9.
94. Kim MS, et al. Histona deacetyieses induce angiogenas~ by negative regulation of tumor suppressor genes. Nature Mad, 2001; 7: 437-443.
95. Kwen HJ et al. HLstona deasetylese inhibitor FK228 inhibitshypoxia-inducad tumor angiogenasis. Nature Med.
96. He LZ, Tolentino T, Grayaon P, et al.: Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 2001, 108: 1321-30.
97. Warrell RP Jr, He LZ, Richon V, et al. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998; 90: 1621-5.
98. Novich S, Camacho L, Gallagher R, et al. Initial clinical evaluation of "transcription therapy" for cancer: all-trans retinoic acid plus phenylbutyrate. Blood 1999; 94: Suppl 1. p61a.
99. O'Connor OA, Kelly W, Wang ES, et al. Clinical development of the histone deacetylase inhibitor suberoylanalide hydroxamic acid (SAHA) in aggressive non-Hodgkin's lymphomas (NHL) and Hodgkin's disease. Blood 2001; 98: 611a.
1. Swirsky DM, Lian YS, Matthews JG, et al. 8:21 translocation in acute granulocytic leukaemia: cytological, cytochemical and clinical features. British Journal of Haematology 1984; 56: 199-213.
2. Ferrara F, Vecchio LD. Acute myloid leukemia with t(8;21)/AML/ETO: a distinct biological and clinical entity. Haematologica 2002; 87: 306-19.
3. Erickson P, Gao J, Chang KS, Look T, et al. Identification of breakpoints in t(8:21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood 1992; 80: 1825-31.
4. Miyoshi H, Kozu T, Shimizu K, et al. 1993 The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. EMBO Journal 12, 2715-21.
5. Ogawa E, Maruyama M, Kagoshima H, et al. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. proceedings of tile, National Academy of Sciences of the United States of America, 1993; 90: 6859-63.
6. Levanon D, Negreanu V, Bernstein Y, et al. AML1, AML2, and AML3, the human members of the runt domain gene family: cDNA structure, expression, and chromosomal localization. Genomics 1994; 23: 425-32.
7. Corsetti MT & Calabi F. Lineage- and stage-specific expression of runt box polypeptides in primitive and definitive hematopoiesis. Blood, 1997; 89: 2359-68.
8. Golling G, Li L, Pepling M, et al. Drosophila homologs of the proto-oncogene product PEBP2/CBF bela regulate the DNA-binding properties of Runt. Molecular and Celhdar Biology 1996; 16: 932-42.
9. Friedman AD. Leukemogenesis by CBF oncoproteins. Leukemia1999; 13: 1932-42.
10. Kania MA, Bonner AS, Duffy JB, et al. The drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in developing nervous system. Genes Dev 1990; 4: 1701-13.
11. Meyers S, Downing JR, Hiebert SW. Identification of AML land the t(8;21) translocation protein AML1-eto as sequence specific DNA binding proteins: the runt domain is required for DNA binding and protein-protein interactions. Mol Cell Biol 1993; 13: 6336-45.
12. Lutterbach B, Hiebert SW. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene 2000; 245: 223-35.
13. Speck NA, Stacy T, Wang Q, et al. Core-binding factor: a central player in hematopoiesis and leukemia. Cancer Res 1999; 59: 1789-93.
14. Uchida H, Zhang J, Nimer SD. AML1A and AML1B can transactivate the human IL-3 promoter. J Immunol 1997; 158: 2251-8.
15. Prosser H.M, WottonD, Gegonne A., et al. A phorbol ester response element within the human T-cell receptor O-chain enhancer. Proceedings of the National Academy of Sciences of the United States of America 1992; 89: 9934-38.
16. Takahashi A, Satake M, Yamaguchi-Iwai Y, et al. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood 1995; 86: 607-16.
17. Wotton D, Ghysdael J, Wang S,et al. Cooperative binding of Ets-1 and core binding factor to DNA.Molecular and Cellular Biology 1994; 14, 840-50.
18. Zhang DE, Hohaus S, Voso MT, et al. (b) Function of PU. 1 (Spi-1), C/EBP, and AML1 in early myelopoiesis: regulation of multiple myeloid CSF receptor promoters. Current Topics in Microbiology and Immunology 1996211, 137-47.
19. Lutterbach B, Westendorf JJ, Linggi B, et al. A mechanism oftranscriptional repression by AML1, the target of multiple chromosome translocations in leukemia. J Biol Chem 2000; 275: 651-6.
20. Britos-Bray, M. & Friedman, A.D. Core binding factor cannot synergistically activate the myeloperoxidase proximal enhancer in immature myeloid cells without c-Myb. Molecular and Cellular Biology 1997; 17: 5127-35.
21. Petrovick MS, Hiebert SW, Friedman AD, et al. Multiple functional domains of AMLI: PU. 1 and C/EBPa synergize with different regions of AML1. Mol Cellular Bio 1998; 18: 3915-25.
22. Kitabayashi I, Yokoyama A, Shimizu K, et al. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO 1998; 17: 2994-3004.
23. Chen H, Lin RJ, Schlitz RL, et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 1997; 90: 569-80.
24. Gu W, & Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997; 90: 595-606.
25. Zhang DE, Hetherington CJ, Meyers S, et al. CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Molecular and Cellular Biology 1996; 16: 1231-40.
26. Zhang YW, Bae SC, Huang G, et al. A novel transcript encoding an N-terminally truncated AML1/PEBP2 alphaB protein interferes with transactivation and blocks granulocytic differentiation of 32Dc13 myeloid cells. Molecular and Cellular Biology 1997; 17: 4133-45.
27. Wang Q, Stacy T, Binder M, et al. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Pro Nati Aca Sci USA 1996; 93: 3444-9.
28. Wang Q, Stacy T, Miller JD, et al. The CBFbeta subunit is essential forCBFalpha2 (AML1) function in vivo. Cell 199687, 697-708.
29. Okada T, van Deursen J, Hiebert SW, et al. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell, 1996; 84: 321-30.
30. Roumier C, Fenaux P, Lafage M, et al. New mechanisms of AML1 gene alteration in hematological malignancies.Leukemia. 2003; 17: 9-16.
31. Okuda T, Cai Z, Yang S et al. Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 1998; 91: 3134-43.
32. Mukouyama Y, Chiba N, Hara T, The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad-mesonephros region. Dev Biol 2000; 220: 27-36
33. Wolford JK, Prochazka M. Structure and expression of the human MTG8/ETO gene. Gene 1998; 212: 103-9
34. Feinstein EG, Kornfield K, Hogness DS, et al. Identification of homeotic target genes in Drosophila melanogaster including nervg a proto-oncogene homologue. Genetics 1995; 140: 573-86.
35. Kitabayashi I, Ida K, Morohoshi E, et al. The AML1-MTG8 leukemic fusion protein forms a complex with a novel member of the MTG8(ETO/CDR) family, MTGR 1. Mol Cell Biol 1998; 18: 846-58.
36. Era T, Asou N, Kunisada T, et al. Identification of two transcripts of AML1/EYO-fused gene in t(8;21) leukemic cells and expression of wild-type ETO gene in hematopoietic cells. Genes, Chromo Cancer, 199513, 25-33.
37. Wang J, Hoshino T, Redner RL, et al. ETO, fusion partner in t(8:21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC 1 complex. Pro Nati Aca Sci USA 1998; 95: 10860-65.
38. Lutterbach B, Westendorf JJ, Linggi B, et al. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol 1998; 18: 7176-84.
39. Zhang J, Hug BA, Huang EY, et al. Oligomerization of ETO is obligatory for corepressor interaction Mol Cell Biol 2001; 21: 156-63.
40. Hildebrand D, Tiefenbach J, Heinzel T, et al. Multiple regions of ETO cooperate in transcriptional repression. J Biol Chem 2001; 276: 9889-95.
41. Meyers S, Lenny N, & Hiebert SW. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol. 1995; 15: 1974-1982.
42. Frank R, Zhang J, Uchida H, The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AMLIB. Onco Gene 1995; 11: 2667-74.
43. Hug BA, Lee SY, Kinsler EL, Cooperative function of AML1-ETO corepressor recruitment domains in the expansion of primary bone marrow cells. Cancer Res. 2002 May 15; 62(10): 2906-12.
44. Da Silva N, Meyer-Monard S, Menot ML, Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO. Hematol J. 2000; 1(5): 316-28.
45. Mulloy JC, Cammenga J, MacKenzie KL, The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood. 2002; 99: 15-23.
46. Lutterbach B, Sun D, Schuetz J et al. The MYND motif is required for repression of basal transcription from the multidrug resistance 1 promoter by the t(8;21) fusion protein. Mol Cell Biol 1998; 18: 3604-11.
47. Schwieger M, Lohler J, Friel J, AML1-ETO inhibits maturation of multiple lymphohematopoietic lineages and induces myeloblast transformation in synergy with ICSBP deficiency. J Exp Med. 2002; 196: 1227-40.
48. Vangala RK, Heiss-Neumann MS, Rangatia JS, The myeloid master regulator transcription factor PU. 1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood. 2003; 101: 270-7.
49. Tanaka K, Tanaka T, Kurokawa M, et al. The AML1/ETO(MTGS) and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2beta(CBFbeta) in the nucleus more efficiently than wild-type AML1. Blood 1998; 91: 1688-99.
50. Chen LE, lto K, Murakami y, et al. The capacity of polyomavirus enhancer binding protein 2aB (AML1/Cbfa2) to stimulate polyomavirus DNA replication is related to its affinity for the nuclear matrix. Mol Cell Biol 1998; 18: 4165-76.
51. Banker DE, Radich J, Becker A, et al. The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults. Clin Cancer Res 1998; 4: 3051-62.
52. Yergeau DA, Hetherington CJ, Wang Q, et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nature Gene1997; 15: 303-6.
53. Westendorf JJ, Yamamoto CM, Lenny N, et al. The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Mol Cell Biol 1998; 18: 322-33.
54. Wang J, Wang M & Liu JM. Transformation properties of the ETO gene, fusion partner in t(8;21) leukemias. Cancer Res 1997; 57: 2951-55.
55. Barseguian K, Lutterbach B, Hiebert SW, et al. Multiple subnuclear targeting signals of the leukemia-related AML1/ETO and ETO repressor proteins. Pro Nati Aca Sci USA 2002; 99: 15434-39.
56. Miyamoto T, Weissman IL, Akashi K. et al. AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation.Proc Natl Acad Sci U S A. 2000 Jun 20; 97(13): 7521-6.
57. Burel SA, Harakawa N, Zhou L, et al. Dichotomy of AML1-ETO functions: growth arrest versus block of differentiation. Mol Cell Biol 2002; 21: 5577-90.
58. Asou H, Tashiro S, Hamamoto K, et al. Establishment of a human acute myeloid leukemia cell line (Kasumi-1) with 8;21 chromosome translocation. Blood 1991 May 1; 77(9): 2031-6
59. Matozaki S, Nakagawa T, Kawaguchi R, et al. Establishment of a myeloid leukaemic cell line (SKNO-1) from a patient with t(8;21) who acquired monosomy 17 during disease progression. Br J Haematol 1995 Apr; 89(4): 805-11.
60. Melnick A, Carlile GW, McConnell MJ, AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein. Blood 2000; 96: 3939-47
61. Kurokawa M, Tanaka T, Tanaka K, et al. Overexpression of the AML1 proto-oncoprotein in NIH3T3 cells leads to neoplastic transformation depending on the DNA-binding and transactivational potencies. Oncogene 1996; 12: 883-92.
62. Namba K, Abe M, Saito S, et al. Indispensable role of the transcription factor PEBP2/CBF in angiogenic activity of a murine endothelial cell MSS31. Oncogene 2000; 19: 106-14.
63. Hwang ES, Hong JH, Bae SC, et al. Regulation of c-fos gene transcription and myeloid cell differentiation by acute myeloid leukemia 1 and acute myeloid leukemia-MTG8, a chimeric leukemogenic derivative of acute myeloid leukemia 1. FEBS Lett 1999 Mar 5; 446(1): 86-90
64. Strom DK, Nip J, et al. Westendorf JJ, et al. Expression of the AML-1 oncogene shortens the G(1) phase of the cell cycle. J Biol Chem 2000; 275: 3438-45
65. Rahoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role ofAML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood 2000; 96: 2108-15.
66. Yuan Y, Zhou L, Miyamoto T, et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci U S A. 2001; 98: 10398-403.
67. DeGuzman CG, Warren AJ, Zhang Z, Hematopoietic stem cell expansion and distinct myeloid developmental abnormalities in a murine model of the AML1-ETO translocation. Mol Cell Biol. 2002 Aug; 22(15): 5506-17.
68. Higuchi M, O'Brien D, Kumaravelu P, Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia.Cancer Cell. 2002 Feb; 1(1): 63-74.
69. Pabst T, Mueller BU, Harakawa N, et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001 Apr; 7(4): 444-51.
70. Rhoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood. 2000 Sep 15; 96(6): 2108-15.