急性髓系白血病发病机制的研究进展
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摘要
急性髓系白血病(acute myeloid leukemia,AML)是白血病中最常见的类型。传统治疗以联合化疗为主,而患者完全缓解率和长期无病生存率均较低。随着研究的深入,发现AML主要的发病机制包括融合基因、信号通路、白血病干细胞(leukemia stem cells,LSCs)以及骨髓微环境的改变等。该文旨在总结目前AML发生、发展机制的研究进展,并探讨其未来可能的治疗研究方向。
Acute myeloid leukemia(AML) is one of the most common malignant tumors. Traditional treatment is given priority to with combination chemotherapy, but complete remission or long-term disease-free survival rate is very low. With further investigation on the advanced research, it is stated that the major pathogenesis of AML include fusion gene, signal pathway, leukemia stem cells(LSCs) and bone marrow niche change. The main aim of this review is to summarize recent advanced development on AML mechanism and to further discuss the potential approaches to the treatment of AML.
Acute myeloid leukemia(AML) is one of the most common malignant tumors. Traditional treatment is given priority to with combination chemotherapy, but complete remission or long-term disease-free survival rate is very low. With further investigation on the advanced research, it is stated that the major pathogenesis of AML include fusion gene, signal pathway, leukemia stem cells(LSCs) and bone marrow niche change. The main aim of this review is to summarize recent advanced development on AML mechanism and to further discuss the potential approaches to the treatment of AML.
引文
1张阳,郑智博,贾学渊,孙文靖,金焰.白血病中融合基因的研究进展.国际遗传学杂志(Zhang Yang,Zheng Zhibo,Jia Xueyuan,Sun Wenjing,Jin Yan.Research progress of fusion genes in leukemia.International Journal of Genetics)2015;38(4):214-8.
2 肖恒,李守霞.白血病融合基因及检测方法研究进展.医学综述(Xiao Heng,Li Shouxia.Advances in leukemia fusion gene and the detection technology.Medical Recapitulate)2015;21(22):4130-3.
3 Marschalek R.MLL leukemia and future treatment strategies.Archiv der Pharmazie 2015;348(4):221-8.
4 Takagi K,Tasaki T,Yamauchi T,Iwasaki H,Ueda T.Successful administration of recombinant human soluble thrombomodulin alpha(recomodulin)for disseminated intravascular coagulation during induction chemotherapy in an elderly patient with acute monoblastic leukemia involving the t(9;11)(p22;q23)MLL/AF9translocation.Case Rep Hematol 2011;2011:273070.
5 Pigneux A,Labopin M,Maertens J,Cordonnier C,Volin L,Socie G,et al.Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement(MLL-r AML).Leukemia 2015;29(12):2375-81.
6 Bindels EM,Havermans M,Lugthart S,Erpelinck C,Wocjtowicz E,Krivtsov AV,et al.EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs.Blood 2012;119(24):5838-49.
7 Beez S,Demmer P,Puccetti E.Targeting the acute promyelocytic leukemia-associated fusion proteins PML/RARalpha and PLZF/RARalpha with interfering peptides.PLo S One 2012;7(11):e48636.
8 Pu LF,Tao QS,Wang HP,Zhai ZM,Xiong SD.The first switched time of PML/RARalpha fusion gene in patients with acute promyelocytic leukemia and its clinical significance.Zhongguo Shi Yan Xue Ye Xue Za Zhi 2015;23(6):1551-5.
9 De Braekeleer E,Douet-Guilbert N,De Braekeleer M.RARA fusion genes in acute promyelocytic leukemia:a review.Exp Rev Hematol 2014;7(3):347-57.
10 Hatlen MA,Wang L,Nimer SD.AML1-ETO driven acute leukemia:insights into pathogenesis and potential therapeutic approaches.Front Med 2012,6(3):248-62.
11 Fu L,Huang W,Jing Y,Jiang M,Zhao Y,Shi J,et al.AML1-ETO triggers epigenetic activation of early growth response gene l,inducing apoptosis in t(8;21)acute myeloid leukemia.FEBS J2014;281(4):1123-31.
12 Tian Y,Wang G,Hu Q,Xiao X,Chen S.AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer.J Cell Biochem 2018;119:3706-15.
13 Xie HM,Gao L,Wang N,Xu YY,Li YH,Yu L,et al.GATA-2gene overexpression and its clinical significance in acute myeloid leukemia with AML1/ETO fusion gene.Sichuan Da Xue Xue Bao Yi Xue Ban 2014;45(4):664-9.
14 Ma ESK,Wan TSK,Au CH,Ho DN,Ma SY,Ng MHL,et al.Next-generation sequencing and molecular cytogenetic characterization of ETV6-LYN fusion due to chromosomes 1,8and 12 rearrangement in acute myeloid leukemia.Cancer Genet2017;218/219:15-9.
15 Wang YY,Ding WJ,Jiang F,Chen ZX,Cen JN,Qi XF,et al.Coexistence of p210(BCR-ABL)and CBFbeta-MYH11 fusion genes in myeloid leukemia:a report of 4 cases.Oncol Lett 2017;14(5):5171-8.
16 Iijima-Yamashita Y,Matsuo H,Yamada M,Deguchi T,Kiyokawa N,Shimada A,et al.Multiplex fusion gene testing in pediatric acute myeloid leukemia.Pediatr Int 2018;60(1):47-51.
17 Shen L,Zhu J,Chen F,Lin W,Cai J,Zhong J,Zhong H.RUNX1-Evi-1 fusion gene inhibited differentiation and apoptosis in myelopoiesis:an in vivo study.BMC Cancer 2015;15:970.
18 Shiba N,Ichikawa H,Taki T,Park MJ,Jo A,Mitani S,et al.NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia.Genes Chromosomes Cancer2013;52(7):683-93.
19 Konig H,Levis M.Targeting FLT3 to treat leukemia.Expert Opin Ther Targets 2015;19(1):37-54.
20 El Hajj H,Dassouki Z,Berthier C,Raffoux E,Ades L,Legrand O,et al.Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1,resulting in apoptosis of AML cells.Blood 2015;125(22):3447-54.
21 Gordon PM,Dias S,Williams DA.Cytokines secreted by bone marrow stromal cells protect c-KIT mutant AML cells from c-KIT inhibitor-induced apoptosis.Leukemia 2014;28(11):2257-60.
22 Bernot KM,Siebenaler RF,Whitman SP,Zorko NA,Marcucci GG,Santhanam R,et al.Toward personalized therapy in AML:in vivo benefit of targeting aberrant epigenetics in MLL-PTDassociated AML.Leukemia 2013;27(12):2379-82.
23 罗兰,万伍卿.白血病干细胞与Wnt/β-catenin信号传导通路.中国医师杂志(Luo Lan,Wan Wuqing.Leukemia stem cells and Wnt/β-catenin signaling pathway.Journal of Chinese Physician)2010:1293-5.
24 Ma S,Yang LL,Niu T,Cheng C,Zhong L,Zheng MW,et al.SKLB-677,an FLT3 and Wnt/beta-catenin signaling inhibitor,displays potent activity in models of FLT3-driven AML.Sci Rep2015;5:15646.
25 Hubbard PA,Moody CL,Murali R.Allosteric modulation of Ras and the PI3K/AKT/m TOR pathway:emerging therapeutic opportunities.Front Physiol 2014;5:478.
26 Sokolowski KM,Koprowski S,Kunnimalaiyaan S,Balamurugan M,Gamblin TC,Kunnimalaiyaan M.Potential molecular targeted therapeutics:role of PI3-K/Akt/m TOR inhibition in cancer.Anticancer Agents Med Chem 2016;16(1):29-37.
27 彭琪,佘妙容,夏平方.磷脂酰肌醇3-激酶/蛋白激酶B信号通路与白血病干细胞耐药的研究进展.中国输血杂志(Peng Qi,She Miaorong,Xia Pingfang.Research progress of phosphatidylinositol 3-kinase/protein kinase B signaling pathway and drug resistance of leukemia stem cells.Chin J Blood Transfusion)2012;25(6):598-601.
28 刘新利,李静,章骏.NF-κB信号与白血病.中国细胞生物学学报(Li Xinli,Li Jing,Zhang Jun.NF-κB signaling and leukemia.Chinese Journal of Cell Biology)2013;35(4):516-25.
29 Kagoya Y,Yoshimi A,Kataoka K,Nakagawa M,Kumano K,Arai S,et al.Positive feedback between NF-kappa B and TNFalpha promotes leukemia-initiating cell capacity.J Clin Invest2014;124(2):528-42.
30 Li J,Volk A,Zhang J,Cannova J,Dai S,Hao C,et al.Sensitizing leukemia stem cells to NF-kappa B inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling.Oncotarget 2017;8(5):8420-35.
31 Volk A,Li J,Xin J,You D,Zhang J,Liu X,et al.Co-inhibition of NF-kappa B and JNK is synergistic in TNF-expressing human AML.J Exp Med 2014;211(6):1093-108.
32 张斌,钟德玝,王群伟,苗雄鹰,戴卫东,刘春,等.JAK/STAT信号通路与肝细胞性肝癌的肿瘤进展和预后的相关性研究.细胞与分子免疫学杂志(Zhang Bin,Zhong Dewu,Wang Qunwei,Miao Xiongying,Dai Weidong,Liu Chun,et al.Study on correlation of JAK/STAT sig-nal pathway with progression and prog-nosis in hepatocellular carcinoma.Chinese Journal of Cellular and Molecular Immunology)2010;26(4):368-70,73.
33 唐志斌,杨彩云,陈志伟,吴秀珍,唐涛,梁先勇.骨肉瘤组织中Ezrin蛋白、E-钙粘蛋白的表达及临床意义.湘南学院学报(医学版)(Tang Zhibin,Yang Caiyun,Chen Zhiwei,Wu Xiuzhen,Tang Tao,Liang Xianyong.Expression of Ezrin protein and E-cadherin in osteosarcoma tissues and their clinical significance.Journal of Xiangnan University,Medical Sciences)2016;18(2):9-12.
34 Cook AM,Li L,Ho Y,Lin A,Li L,Stein A,et al.Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells.Blood2014,123(18):2826-37.
35 李英华,罗建民.白血病形成中JAK/STAT信号通路的持续激活.国际病理科学与临床杂志(Li Yinghua,Luo Jianmin.Constitutive activation of JAK/STAT signaling pathway in leukemogenesis.International Journal of Pathology and Clinical Medicine)2006;26(5):398-402.
36 Stubig T,Alchalby H,Ditschkowski M,Wolf D,Wulf G,Zabelina T,et al.JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis.Leukemia 2014;28(8):1736-8.
37 Juen L,Brachet-Botineau M,Parmenon C,Bourgeais J,Herault O,Gouilleux F,et al.New inhibitor targeting signal transducer and activator of transcription 5(STAT5)signaling in myeloid leukemias.J Med Chem 2017;60(14):6119-36.
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2 肖恒,李守霞.白血病融合基因及检测方法研究进展.医学综述(Xiao Heng,Li Shouxia.Advances in leukemia fusion gene and the detection technology.Medical Recapitulate)2015;21(22):4130-3.
3 Marschalek R.MLL leukemia and future treatment strategies.Archiv der Pharmazie 2015;348(4):221-8.
4 Takagi K,Tasaki T,Yamauchi T,Iwasaki H,Ueda T.Successful administration of recombinant human soluble thrombomodulin alpha(recomodulin)for disseminated intravascular coagulation during induction chemotherapy in an elderly patient with acute monoblastic leukemia involving the t(9;11)(p22;q23)MLL/AF9translocation.Case Rep Hematol 2011;2011:273070.
5 Pigneux A,Labopin M,Maertens J,Cordonnier C,Volin L,Socie G,et al.Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement(MLL-r AML).Leukemia 2015;29(12):2375-81.
6 Bindels EM,Havermans M,Lugthart S,Erpelinck C,Wocjtowicz E,Krivtsov AV,et al.EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs.Blood 2012;119(24):5838-49.
7 Beez S,Demmer P,Puccetti E.Targeting the acute promyelocytic leukemia-associated fusion proteins PML/RARalpha and PLZF/RARalpha with interfering peptides.PLo S One 2012;7(11):e48636.
8 Pu LF,Tao QS,Wang HP,Zhai ZM,Xiong SD.The first switched time of PML/RARalpha fusion gene in patients with acute promyelocytic leukemia and its clinical significance.Zhongguo Shi Yan Xue Ye Xue Za Zhi 2015;23(6):1551-5.
9 De Braekeleer E,Douet-Guilbert N,De Braekeleer M.RARA fusion genes in acute promyelocytic leukemia:a review.Exp Rev Hematol 2014;7(3):347-57.
10 Hatlen MA,Wang L,Nimer SD.AML1-ETO driven acute leukemia:insights into pathogenesis and potential therapeutic approaches.Front Med 2012,6(3):248-62.
11 Fu L,Huang W,Jing Y,Jiang M,Zhao Y,Shi J,et al.AML1-ETO triggers epigenetic activation of early growth response gene l,inducing apoptosis in t(8;21)acute myeloid leukemia.FEBS J2014;281(4):1123-31.
12 Tian Y,Wang G,Hu Q,Xiao X,Chen S.AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer.J Cell Biochem 2018;119:3706-15.
13 Xie HM,Gao L,Wang N,Xu YY,Li YH,Yu L,et al.GATA-2gene overexpression and its clinical significance in acute myeloid leukemia with AML1/ETO fusion gene.Sichuan Da Xue Xue Bao Yi Xue Ban 2014;45(4):664-9.
14 Ma ESK,Wan TSK,Au CH,Ho DN,Ma SY,Ng MHL,et al.Next-generation sequencing and molecular cytogenetic characterization of ETV6-LYN fusion due to chromosomes 1,8and 12 rearrangement in acute myeloid leukemia.Cancer Genet2017;218/219:15-9.
15 Wang YY,Ding WJ,Jiang F,Chen ZX,Cen JN,Qi XF,et al.Coexistence of p210(BCR-ABL)and CBFbeta-MYH11 fusion genes in myeloid leukemia:a report of 4 cases.Oncol Lett 2017;14(5):5171-8.
16 Iijima-Yamashita Y,Matsuo H,Yamada M,Deguchi T,Kiyokawa N,Shimada A,et al.Multiplex fusion gene testing in pediatric acute myeloid leukemia.Pediatr Int 2018;60(1):47-51.
17 Shen L,Zhu J,Chen F,Lin W,Cai J,Zhong J,Zhong H.RUNX1-Evi-1 fusion gene inhibited differentiation and apoptosis in myelopoiesis:an in vivo study.BMC Cancer 2015;15:970.
18 Shiba N,Ichikawa H,Taki T,Park MJ,Jo A,Mitani S,et al.NUP98-NSD1 gene fusion and its related gene expression signature are strongly associated with a poor prognosis in pediatric acute myeloid leukemia.Genes Chromosomes Cancer2013;52(7):683-93.
19 Konig H,Levis M.Targeting FLT3 to treat leukemia.Expert Opin Ther Targets 2015;19(1):37-54.
20 El Hajj H,Dassouki Z,Berthier C,Raffoux E,Ades L,Legrand O,et al.Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1,resulting in apoptosis of AML cells.Blood 2015;125(22):3447-54.
21 Gordon PM,Dias S,Williams DA.Cytokines secreted by bone marrow stromal cells protect c-KIT mutant AML cells from c-KIT inhibitor-induced apoptosis.Leukemia 2014;28(11):2257-60.
22 Bernot KM,Siebenaler RF,Whitman SP,Zorko NA,Marcucci GG,Santhanam R,et al.Toward personalized therapy in AML:in vivo benefit of targeting aberrant epigenetics in MLL-PTDassociated AML.Leukemia 2013;27(12):2379-82.
23 罗兰,万伍卿.白血病干细胞与Wnt/β-catenin信号传导通路.中国医师杂志(Luo Lan,Wan Wuqing.Leukemia stem cells and Wnt/β-catenin signaling pathway.Journal of Chinese Physician)2010:1293-5.
24 Ma S,Yang LL,Niu T,Cheng C,Zhong L,Zheng MW,et al.SKLB-677,an FLT3 and Wnt/beta-catenin signaling inhibitor,displays potent activity in models of FLT3-driven AML.Sci Rep2015;5:15646.
25 Hubbard PA,Moody CL,Murali R.Allosteric modulation of Ras and the PI3K/AKT/m TOR pathway:emerging therapeutic opportunities.Front Physiol 2014;5:478.
26 Sokolowski KM,Koprowski S,Kunnimalaiyaan S,Balamurugan M,Gamblin TC,Kunnimalaiyaan M.Potential molecular targeted therapeutics:role of PI3-K/Akt/m TOR inhibition in cancer.Anticancer Agents Med Chem 2016;16(1):29-37.
27 彭琪,佘妙容,夏平方.磷脂酰肌醇3-激酶/蛋白激酶B信号通路与白血病干细胞耐药的研究进展.中国输血杂志(Peng Qi,She Miaorong,Xia Pingfang.Research progress of phosphatidylinositol 3-kinase/protein kinase B signaling pathway and drug resistance of leukemia stem cells.Chin J Blood Transfusion)2012;25(6):598-601.
28 刘新利,李静,章骏.NF-κB信号与白血病.中国细胞生物学学报(Li Xinli,Li Jing,Zhang Jun.NF-κB signaling and leukemia.Chinese Journal of Cell Biology)2013;35(4):516-25.
29 Kagoya Y,Yoshimi A,Kataoka K,Nakagawa M,Kumano K,Arai S,et al.Positive feedback between NF-kappa B and TNFalpha promotes leukemia-initiating cell capacity.J Clin Invest2014;124(2):528-42.
30 Li J,Volk A,Zhang J,Cannova J,Dai S,Hao C,et al.Sensitizing leukemia stem cells to NF-kappa B inhibitor treatment in vivo by inactivation of both TNF and IL-1 signaling.Oncotarget 2017;8(5):8420-35.
31 Volk A,Li J,Xin J,You D,Zhang J,Liu X,et al.Co-inhibition of NF-kappa B and JNK is synergistic in TNF-expressing human AML.J Exp Med 2014;211(6):1093-108.
32 张斌,钟德玝,王群伟,苗雄鹰,戴卫东,刘春,等.JAK/STAT信号通路与肝细胞性肝癌的肿瘤进展和预后的相关性研究.细胞与分子免疫学杂志(Zhang Bin,Zhong Dewu,Wang Qunwei,Miao Xiongying,Dai Weidong,Liu Chun,et al.Study on correlation of JAK/STAT sig-nal pathway with progression and prog-nosis in hepatocellular carcinoma.Chinese Journal of Cellular and Molecular Immunology)2010;26(4):368-70,73.
33 唐志斌,杨彩云,陈志伟,吴秀珍,唐涛,梁先勇.骨肉瘤组织中Ezrin蛋白、E-钙粘蛋白的表达及临床意义.湘南学院学报(医学版)(Tang Zhibin,Yang Caiyun,Chen Zhiwei,Wu Xiuzhen,Tang Tao,Liang Xianyong.Expression of Ezrin protein and E-cadherin in osteosarcoma tissues and their clinical significance.Journal of Xiangnan University,Medical Sciences)2016;18(2):9-12.
34 Cook AM,Li L,Ho Y,Lin A,Li L,Stein A,et al.Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells.Blood2014,123(18):2826-37.
35 李英华,罗建民.白血病形成中JAK/STAT信号通路的持续激活.国际病理科学与临床杂志(Li Yinghua,Luo Jianmin.Constitutive activation of JAK/STAT signaling pathway in leukemogenesis.International Journal of Pathology and Clinical Medicine)2006;26(5):398-402.
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