Leukemogenic potency of the novel FLT3-N676K mutant

详细信息    查看全文

• 作者：Kezhi Huang ; Min Yang ; Zengkai Pan ; Florian H. Heidel…
• 关键词：Acute leukemia ; FLT3 ; N676K ; FLT3 mutations ; inv(16) ; FLT3 inhibitors
• 刊名：Annals of Hematology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：95
• 期：5
• 页码：783-791
• 全文大小：625 KB
• 参考文献：1.Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411(6835):355–365CrossRef PubMed
  2.Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE (2007) FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood 110(4):1262–1270CrossRef PubMed
  3.Chalandon Y, Schwaller J (2005) Targeting mutated protein tyrosine kinases and their signaling pathways in hematologic malignancies. Haematologica 90(7):949–968PubMed
  4.Dohner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 373(12):1136–1152CrossRef PubMed
  5.Santos FP, Jones D, Qiao W, Cortes JE, Ravandi F, Estey EE, Verma D, Kantarjian H, Borthakur G (2011) Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia. Cancer 117(10):2145–2155CrossRef PubMed PubMedCentral
  6.Paschka P, Du J, Schlenk RF, Gaidzik VI, Bullinger L, Corbacioglu A, Spath D, Kayser S, Schlegelberger B, Krauter J, Ganser A, Kohne CH, Held G, von Lilienfeld-Toal M, Kirchen H, Rummel M, Gotze K, Horst HA, Ringhoffer M, Lubbert M, Wattad M, Salih HR, Kundgen A, Dohner H, Dohner K (2013) Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG). Blood 121(1):170–177CrossRef PubMed
  7.Kindler T, Lipka DB, Fischer T (2010) FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 116(24):5089–5102CrossRef PubMed
  8.Falini B, Sportoletti P, Brunetti L, Martelli MP (2015) Perspectives for therapeutic targeting of gene mutations in acute myeloid leukaemia with normal cytogenetics. Br J Haematol 170(3):305–322CrossRef PubMed
  9.Opatz S, Polzer H, Herold T, Konstandin NP, Ksienzyk B, Zellmeier E, Vosberg S, Graf A, Krebs S, Blum H, Hopfner KP, Kakadia PM, Schneider S, Dufour A, Braess J, Sauerland MC, Berdel WE, Buchner T, Woermann BJ, Hiddemann W, Spiekermann K, Bohlander SK, Greif PA (2013) Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia. Blood 122(10):1761–1769CrossRef PubMed
  10.Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede MH, Brandts C, Serve H, Roesel J, Giles F, Feldman E, Ehninger G, Schiller GJ, Nimer S, Stone RM, Wang YF, Kindler T, Cohen PS, Huber C, Fischer T (2006) Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood 107(1):293–300CrossRef PubMed
  11.Zirm E, Spies-Weisshart B, Heidel F, Schnetzke U, Bohmer FD, Hochhaus A, Fischer T, Scholl S (2012) Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation. Br J Haematol 157(4):483–492CrossRef PubMed
  12.Allen C, Hills RK, Lamb K, Evans C, Tinsley S, Sellar R, O’Brien M, Yin JL, Burnett AK, Linch DC, Gale RE (2013) The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia 27(9):1891–1901CrossRef PubMed
  13.Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG (2002) FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 99(1):310–318CrossRef PubMed
  14.Schambach A, Mueller D, Galla M, Verstegen MM, Wagemaker G, Loew R, Baum C, Bohne J (2006) Overcoming promoter competition in packaging cells improves production of self-inactivating retroviral vectors. Gene Ther 13(21):1524–1533CrossRef PubMed
  15.Li Z, Schwieger M, Lange C, Kraunus J, Sun H, van den Akker E, Modlich U, Serinsoz E, Will E, von Laer D, Stocking C, Fehse B, Schiedlmeier B, Baum C (2003) Predictable and efficient retroviral gene transfer into murine bone marrow repopulating cells using a defined vector dose. Exp Hematol 31(12):1206–1214CrossRef PubMed
  16.Yang M, Huang K, Busche G, Ganser A, Li Z (2014) Activation of TRKB receptor in murine hematopoietic stem/progenitor cells induced mastocytosis. Blood 124(7):1196–1197CrossRef PubMed
  17.Li Z, Kustikova OS, Kamino K, Neumann T, Rhein M, Grassman E, Fehse B, Baum C (2007) Insertional mutagenesis by replication-deficient retroviral vectors encoding the large T oncogene. Ann N Y Acad Sci 1106:95–113CrossRef PubMed
  18.Meyer J, Rhein M, Schiedlmeier B, Kustikova O, Rudolph C, Kamino K, Neumann T, Yang M, Wahlers A, Fehse B, Reuther GW, Schlegelberger B, Ganser A, Baum C, Li Z (2007) Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, deltaTrkA. Leukemia 21(10):2171–2180CrossRef PubMed
  19.Schemionek M, Herrmann O, Merle Reher M, Chatain N, Schubert C, Costa IG, Haenzelmann S, Gusmao EG, Kintsler S, Braunschweig T, Hamilton A, Helgason GV, Copland M, Schwab A, Muller-Tidow C, Li S, Holyoake TL, Brummendorf TH, Koschmieder S (2015) MTSS1 is a critical epigenetically regulated tumor suppressor in CML. Leukemia. doi:10.​1038/​leu.​2015.​329
  20.Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C, Gruning W, Kratz-Albers K, Serve S, Steur C, Buchner T, Kienast J, Kanakura Y, Berdel WE, Serve H (2000) Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 96(12):3907–3914PubMed
  21.Schwieger M, Lohler J, Fischer M, Herwig U, Tenen DG, Stocking C (2004) A dominant-negative mutant of C/EBP alpha, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse. Blood 103(7):2744–2752CrossRef PubMed
  22.Yang M, Busche G, Ganser A, Li Z (2013) Morphology and quantitative composition of hematopoietic cells in murine bone marrow and spleen of healthy subjects. Ann Hematol 92(5):587–594CrossRef PubMed
  23.Yang M, Busche G, Ganser A, Li Z (2013) Cytological characterization of murine bone marrow and spleen hematopoietic compartments for improved assessment of toxicity in preclinical gene marking models. Ann Hematol 92(5):595–604CrossRef PubMed
  24.Meyer J, Jucker M, Ostertag W, Stocking C (1998) Carboxyl-truncated STAT5beta is generated by a nucleus-associated serine protease in early hematopoietic progenitors. Blood 91(6):1901–1908PubMed
  25.Li Z, Dullmann J, Schiedlmeier B, Schmidt M, von Kalle C, Meyer J, Forster M, Stocking C, Wahlers A, Frank O, Ostertag W, Kuhlcke K, Eckert HG, Fehse B, Baum C (2002) Murine leukemia induced by retroviral gene marking. Science 296(5567):497CrossRef PubMed
  26.Zhao L, Melenhorst JJ, Alemu L, Kirby M, Anderson S, Kench M, Hoogstraten-Miller S, Brinster L, Kamikubo Y, Gilliland DG, Liu PP (2012) KIT with D816 mutations cooperates with CBFB-MYH11 for leukemogenesis in mice. Blood 119(6):1511–1521CrossRef PubMed PubMedCentral
  27.Smith CC, Lasater EA, Lin KC, Wang Q, McCreery MQ, Stewart WK, Damon LE, Perl AE, Jeschke GR, Sugita M, Carroll M, Kogan SC, Kuriyan J, Shah NP (2014) Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci U S A 111(14):5319–5324CrossRef PubMed PubMedCentral
  28.Lewis NL, Lewis LD, Eder JP, Reddy NJ, Guo F, Pierce KJ, Olszanski AJ, Cohen RB (2009) Phase I study of the safety, tolerability, and pharmacokinetics of oral CP-868,596, a highly specific platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers. J Clin Oncol 27(31):5262–5269CrossRef PubMed PubMedCentral
  29.Stubbs MC, Kim YM, Krivtsov AV, Wright RD, Feng Z, Agarwal J, Kung AL, Armstrong SA (2008) MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia 22(1):66–77CrossRef PubMed PubMedCentral
  30.Bailey E, Li L, Duffield AS, Ma HS, Huso DL, Small D (2013) FLT3/D835Y mutation knock-in mice display less aggressive disease compared with FLT3/internal tandem duplication (ITD) mice. Proc Natl Acad Sci U S A 110(52):21113–21118CrossRef PubMed PubMedCentral
  31.Talluri S, Francis SM, Dick FA (2013) Mutation of the LXCXE binding cleft of pRb facilitates transformation by ras in vitro but does not promote tumorigenesis in vivo. PLoS One 8(8):e72236CrossRef PubMed PubMedCentral
  32.Cools J, Mentens N, Furet P, Fabbro D, Clark JJ, Griffin JD, Marynen P, Gilliland DG (2004) Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res 64(18):6385–6389CrossRef PubMed
  33.von Bubnoff N, Engh RA, Aberg E, Sanger J, Peschel C, Duyster J (2009) FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. Cancer Res 69(7):3032–3041CrossRef
  34.Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, Perl AE, Travers KJ, Wang S, Hunt JP, Zarrinkar PP, Schadt EE, Kasarskis A, Kuriyan J, Shah NP (2012) Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485(7397):260–263CrossRef PubMed PubMedCentral
  35.Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC, Choi WW, Lok S, Cheung AM, Eaves C, Kwong YL, Leung AY (2012) Sorafenib treatment of FLT3-ITD(+) acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent nonresponsiveness associated with the emergence of a D835 mutation. Blood 119(22):5133–5143CrossRef PubMed
  36.Kim HG, Kojima K, Swindle CS, Cotta CV, Huo Y, Reddy V, Klug CA (2008) FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia. Blood 111(3):1567–1574CrossRef PubMed PubMedCentral
  37.Meyer SC, Levine RL (2014) Translational implications of somatic genomics in acute myeloid leukaemia. Lancet Oncol 15(9):e382–e394CrossRef PubMed
  38.Cancer Genome Atlas Research Network (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 368(22):2059–2074CrossRef
  39.Knoppers BM, Zawati MH, Senecal K (2015) Return of genetic testing results in the era of whole-genome sequencing. Nat Rev Genet 16(9):553–559CrossRef PubMed
  40.Sinha C, Cunningham LC, Liu PP (2015) Core binding factor acute myeloid leukemia: new prognostic categories and therapeutic opportunities. Semin Hematol 52(3):215–222CrossRef PubMed
  
• 作者单位：Kezhi Huang (1) (2)
  Min Yang (1) (2)
  Zengkai Pan (1)
  Florian H. Heidel (3) (4)
  Michaela Scherr (1)
  Matthias Eder (1)
  Thomas Fischer (3)
  Guntram Büsche (5)
  Karl Welte (6)
  Nils von Neuhoff (7)
  Arnold Ganser (1)
  Zhixiong Li (1) (2)
  
  1. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany
  2. Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
  3. Department of Hematology and Oncology, Medical Center, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  4. Internal Medicine II, Hematology and Oncology, University Hospital Jena, Jena, Germany
  5. Institute of Pathology, Hannover Medical School, Hannover, Germany
  6. Department of Molecular Hematopoiesis, Hannover Medical School, Hannover, Germany
  7. Institute of Human Genetics, Hannover Medical School, Hannover, Germany
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Hematology
  Oncology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0584

文摘

The novel FMS-like tyrosine kinase 3 (FLT3)-N676K point mutation within the FLT3 kinase domain-1 was recently identified in 6 % of de novo acute myeloid leukemia (AML) patients with inv(16). Because FLT3-N676K was encountered almost exclusively in inv(16) AML, we investigated the transforming potential of FLT3-N676K, the cooperation between FLT3-N676K and core binding factor ß-smooth muscle myosin heavy chain (CBFß-SMMHC) (encoded by the inv(16) chimeric gene CBFB-MYH11) in inducing acute leukemia, and tested the sensitivity of FLT3-N676K-positive leukemic cells to FLT3 inhibitors. Retroviral expression of FLT3-N676K in myeloid 32D cells induced AML in syngeneic C3H/HeJ mice (n = 11/13, median latency 58 days), with a transforming activity similar to FLT3-internal tandem duplication (ITD) (n = 8/8), FLT3-TKD D835Y (n = 8/9), and FLT3-ITD-N676K (n = 9/9) mutations. Three out of 14 (21.4 %) C57BL/6J mice transplanted with FLT3-N676K-transduced primary hematopoietic progenitor cells developed acute leukemia (latency of 68, 77, and 273 days), while no hematological malignancy was observed in the control groups including FLT3-ITD. Moreover, co-expression of FLT3-N676K/CBFß-SMMHC did not promote acute leukemia in three independent experiments (n = 16). In comparison with FLT3-ITD, FLT3-N676K induced much higher activation of FLT3 and tended to trigger stronger phosphorylation of MAPK and AKT. Importantly, leukemic cells carrying the FLT3-N676K mutant in the absence of an ITD mutation were highly sensitive to FLT3 inhibitors AC220 and crenolanib, and crenolanib even retained activity against the AC220-resistant FLT3-ITD-N676K mutant. Taken together, the FLT3-N676K mutant is potent to transform murine hematopoietic stem/progenitor cells in vivo. This is the first report of acute leukemia induced by an activating FLT3 mutation in C57BL/6J mice. Moreover, further experiments investigating molecular mechanisms for leukemogenesis induced by FLT3-N676K mutation and clinical evaluation of FLT3 inhibitors in FLT3-N676K-positive AML seem warranted.