FLT3 inhibition: A moving and evolving target in acute myeloid leukaemia

Leukemia

Volumn 27, Issue 2, 2013, Pages 260-268

  Leung, A Y H ^a   Man, C H ^a   Kwong, Y L ^a  

^a QUEEN MARY HOSPITAL   (Hong Kong)

Author keywords

[No Author keywords available]

Indexed keywords

1 [5 HYDROXY 2 (2 THIENYL) 4 QUINAZOLINYLAMINO] 3 METHYL 2,5 PYRROLEDIONE; [4 [2 (1H INDAZOL 3 YL)VINYL]PHENYL](1 PIPERAZINYL)METHANONE; ANTILEUKEMIC AGENT; AR 00459339; ATH 686; AUZ 454; BAG 956; BPR1J 097; CANERTINIB; CCT 137690; CD135 ANTIGEN; CYTARABINE; DAUNORUBICIN; ETOPOSIDE; EVEROLIMUS; IDARUBICIN; LESTAURTINIB; LINIFANIB; LY 2457546; MIDOSTAURIN; MITOXANTRONE; PACRITINIB; PONATINIB; QUIZARTINIB; RAPAMYCIN; SELUMETINIB; SEMAXANIB; SKLB 1028; SORAFENIB; SUNITINIB; TANDUTINIB; UNCLASSIFIED DRUG; VORINOSTAT; VX 322;

ACUTE GRANULOCYTIC LEUKEMIA; CANCER GROWTH; CANCER PROGNOSIS; COMPETITIVE INHIBITION; DISEASE ASSOCIATION; DNA REPAIR; DRUG EFFICACY; GAIN OF FUNCTION MUTATION; GENETIC VARIABILITY; HIGH THROUGHPUT SCREENING; HUMAN; IN VITRO STUDY; LEUKEMIA CELL LINE; MUTATIONAL ANALYSIS; PRIORITY JOURNAL; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; TREATMENT RESPONSE; UPREGULATION; XENOTRANSPLANTATION;

ANIMALS; ANTINEOPLASTIC AGENTS; FMS-LIKE TYROSINE KINASE 3; HUMANS; LEUKEMIA, MYELOID, ACUTE;

EID: 84873569249     PISSN: 08876924     EISSN: 14765551     Source Type: Journal    
DOI: 10.1038/leu.2012.195     Document Type: Review

References (118)

1. Rowe JM, Tallman MS. How I treat acute myeloid leukemia. Blood 2010; 116: 3147-3156.
2. Frohling S, Schlenk RF, Breitruck J, Benner A, Kreitmeier S, Tobis K et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100: 4372-4380.
3. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59-66.
4. Meshinchi S, Appelbaum FR. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 2009; 15: 4263-4269.
5. Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 1991; 65: 1143-1152.
6. Choudhary C, Schwable J, Brandts C, Tickenbrock L, Sargin B, Kindler T et al. AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood 2005; 106: 265-273.
7. Rocnik JL, Okabe R, Yu JC, Lee BH, Giese N, Schenkein DP et al. Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD. Blood 2006; 108: 1339-1345.
8. Kiyoi H, Towatari M, Yokota S, Hamaguchi M, Ohno R, Saito H et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 1998; 12: 1333-1337.
9. Leischner H, Albers C, Grundler R, Razumovskaya E, Spiekermann K, Bohlander S et al. SRC is a signaling mediator in FLT3-ITD but not in FLT3-TKD positive AML. Blood 2012; 119: 4026-4033.
10. Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res 2005; 65: 9643-9650.
11. Jin G, Matsushita H, Asai S, Tsukamoto H, Ono R, Nosaka T et al. FLT3-ITD induces ara-C resistance in myeloid leukemic cells through the repression of the ENT1 expression. Biochem Biophys Res Commun 2009; 390: 1001-1006.
12. Sallmyr A, Fan J, Datta K, Kim KT, Grosu D, Shapiro P et al. Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML. Blood 2008; 111: 3173-3182.
13. Rodrigues MS, Reddy MM, Sattler M. Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications. Antioxid Redox Signal 2008; 10: 1813-1848.
14. Choudhary C, Muller-Tidow C, Berdel WE, Serve H. Signal transduction of oncogenic Flt3. Int J Hematol 2005; 82: 93-99.
15. Small D. Targeting FLT3 for the treatment of leukemia. Semin Hematol 2008; 45(Suppl 2): S17-S21.
16. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 2003; 3: 650-665.
17. Kiyoi H, Naoe T, Yokota S, Nakao M, Minami S, Kuriyama K et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia. Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia 1997; 11: 1447-1452.
18. Kiyoi H, Yanada M, Ozekia K. Clinical significance of FLT3 in leukemia. Int J Hematol 2005; 82: 85-92.
19. Sheikhha MH, Awan A, Tobal K, Liu Yin JA. Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol J 2003; 4: 41-46.
20. Meshinchi S, Stirewalt DL, Alonzo TA, Boggon TJ, Gerbing RB, Rocnik JL et al. Structural and numerical variation of FLT3/ITD in pediatric AML. Blood 2008; 111: 4930-4933.
21. Santos FP, Jones D, Qiao W, Cortes JE, RaVandi F, Estey EE et al. Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia. Cancer 2011; 117: 2145-2155.
22. Gale RE, Green C, Allen C, Mead AJ, Burnett AK, Hills RK et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008; 111: 2776-2784.
23. Pemmaraju N, Kantarjian H, RaVandi F, Cortes J. FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an era? Cancer 2011; 117: 3293-3304.
24. Kindler T, Lipka DB, Fischer T. FLT3 as a therapeutic target in AML: still challenging after all these years. Blood 2010; 116: 5089-5102.
25. Knapper S. FLT3 inhibition in acute myeloid leukaemia. Br J Haematol 2007; 138: 687-699.
26. Knapper S. The clinical development of FLT3 inhibitors in acute myeloid leukemia. Expert Opin Invest Drugs 2011; 20: 1377-1395.
27. Fiedler W, Mesters R, Tinnefeld H, Loges S, Staib P, Duhrsen U et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood 2003; 102: 2763-2767.
28. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3. J Clin Oncol 2010; 28: 4339-4345.
29. Levis M, Brown P, Smith BD, Stine A, Pham R, Stone R et al. Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Blood 2006; 108: 3477-3483.
30. Smith BD, Levis M, Beran M, Giles F, Kantarjian H, Berg K et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood 2004; 103: 3669-3676.
31. Stone RM, De Angelo J, Galinsky I, Estey E, Klimek V, Grandin W et al. PKC 412 FLT3 inhibitor therapy in AML: results of a phase II trial. Ann Hematol 2004; 83(Suppl 1): S89-S90.
32. Kojima K, McQueen T, Chen Y, Jacamo R, Konopleva M, Shinojima N et al. P53 activation of mesenchymal stromal cells partially abrogates microenvironmentmediated resistance to FLT3 inhibition in AML through HIF-1alpha-mediated down-regulation of CXCL12. Blood 2011; 118: 4431-4439.
33. Parmar A, Marz S, Rushton S, Holzwarth C, Lind K, Kayser S et al. Stromal niche cells protect early leukemic FLT3-ITD\+ progenitor cells against first-generation FLT3 tyrosine kinase inhibitors. Cancer Res 2011; 71: 4696-4706.
34. Sato T, Yang X, Knapper S, White P, Smith BD, Galkin S et al. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood 2011; 117: 3286-3293.
35. Stolzel F, Steudel C, Oelschlagel U, Mohr B, Koch S, Ehninger G et al. Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. Ann Hematol 2010; 89: 653-662.
36. Weisberg E, Sattler M, Ray A, Griffin JD. Drug resistance in mutant FLT3-positive AML. Oncogene 2010; 29: 5120-5134.
37. Weisberg E, Ray A, Nelson E, Adamia S, Barrett R, Sattler M et al. Reversible resistance induced by FLT3 inhibition: a novel resistance mechanism in mutant FLT3-expressing cells. PLoS One 2011; 6: e25351.
38. Zhou J, Bi C, Janakakumara JV, Liu SC, Chng WJ, Tay KG et al. Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood 2009; 113: 4052-4062.
39. Breitenbuecher F, Markova B, Kasper S, Carius B, Stauder T, Bohmer FD et al. A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML. Blood 2009; 113: 4063-4073.
40. Greaves M, Maley CC. Clonal evolution in cancer. Nature 2012; 481: 306-313.
41. Apperley JF, Part I. mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8: 1018-1029.
42. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 2008; 8: 755-768.
43. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98: 1752-1759.
44. Shih LY, Huang CF, Wu JH, Lin TL, Dunn P, Wang PN et al. Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood 2002; 100: 2387-2392.
45. Levis M, Murphy KM, Pham R, Kim KT, Stine A, Li L et al. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood 2005; 106: 673-680.
46. Cheung AM, Chow HC, Kwong YL, Liang R, Leung AY. FLT3/internal tandem duplication subclones in acute myeloid leukemia differ in their engraftment potential in NOD/SCID mice. Leuk Res 2010; 34: 119-122.
47. Greenblatt S, Li L, Slape C, Nguyen B, Novak R, Duffield A et al. Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model. Blood 2012; 119: 2883-2894.
48. Tam WF, Gary Gilliland D. Can FLT3 inhibitors overcome resistance in AML? Best Pract Res Clin Haematol 2008; 21: 13-20.
49. Levis M, RaVandi F, Wang ES, Baer MR, Perl A, Coutre S et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 2011; 117: 3294-3301.
50. DeAngelo DJ, Stone RM, Heaney ML, Nimer SD, Paquette RL, Klisovic RB et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood 2006; 108: 3674-3681.
51. Fiedler W, Serve H, Dohner H, Schwittay M, Ottmann OG, O'Farrell AM et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005; 105: 986-993.
52. Pratz KW Cortes J, Roboz GJ, Rao N, Arowojolu O, Stine A et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 2009; 113: 3938-3946.
53. Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst 2008; 100: 184-198.
54. Cortes JE, Perl AE, Smith CC, Kovacsovics T, Dombret H, Dohner H et al. A phase II open-label, Ac220 monotherapy efficacy study in patients with refractory/relapsed Flt3-Itd positive acute myeloid leukemia: updated interim results. ASH Annual Meeting Abstracts 2011; 118: 2576.
55. RaVandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 2010; 28: 1856-1862.
56. Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 2012; e-pub ahead of print 27 April 2012; doi:10.1038/leu.2012.115.
57. Grundler R, Miething C, Thiede C, Peschel C, Duyster J. FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood 2005; 105: 4792-4799.
58. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosomepositive leukaemias. Lancet Oncol 2003; 4: 75-85.
59. Heidel F, Solem FK, Breitenbuecher F, Lipka DB, Kasper S, Thiede MH et al. Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. Blood 2006; 107: 293-300.
60. von Bubnoff N, Rummelt C, Menzel H, Sigl M, Peschel C, Duyster J. Identification of a secondary FLT3/A848P mutation in a patient with FLT3-ITD-positive blast phase CMML and response to sunitinib and sorafenib. Leukemia 2010; 24: 1523-1525.
61. Man CH, Fung TK, Ho C, Han HH, Chow HC, Ma AC et al. Sorafenib treatment of FLT3-ITD\+ acute myeloid leukemia: favorable initial outcome and mechanisms of subsequent non-responsiveness associated with a D835 mutation. Blood 2012; 119: 5133-5143.
62. Alvarado Y, Kantarjian HM, RaVandi F, Luthra R, Borthakur G, Garcia Manero G et al. FLT3 inhibitor treatment in FLT3-mutated AML is associated with development of secondary FLT3-TKD mutations. ASH Annual Meeting Abstracts 2011; 118: 1493.
63. Zhang W, Konopleva M, Jacamo RO, Borthakur G, Chen W, Cortes JE et al. Acquired point mutations of TKD are responsible for sorafenib resistance in FLT3-ITD mutant AML. ASH Annual Meeting Abstracts 2011; 118: 3505.
64. Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 2012; 485: 260-263.
65. Moore AS, Faisal A, de Castro DG, Bavetsias V, Sun C, Atrash B et al. Selective FLT3 inhibition of FLT3-ITD(\+) acute myeloid leukaemia resulting in secondary D835Y mutation: a modelfor emerging clinical resistance patterns. Leukemia 2012; 26: 1462-1470.
66. Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481: 506-510.
67. Kojima K, Konopleva M, Tsao T, Andreeff M, Ishida H, Shiotsu Y et al. Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis. Leukemia 2010; 24: 33-43.
68. Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood 2009; 114: 1607-1617.
69. Lainey E, Thepot S, Bouteloup C, Sebert M, Ades L, Tailler M et al. Tyrosine kinase inhibitors for the treatment of acute myeloid leukemia: delineation of anti-leukemic mechanisms of action. Biochem Pharmacol 2011; 82: 1457-1466.
70. Grundler R, Thiede C, Miething C, Steudel C, Peschel C, Duyster J. Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor. Blood 2003; 102: 646-651.
71. Bagrintseva K, Geisenhof S, Kern R, Eichenlaub S, Reindl C, Ellwart JW et al. FLT3-ITD-TKD dual mutants associated with AML confer resistance to FLT3 PTK inhibitors and cytotoxic agents by overexpression of Bcl-x(L). Blood 2005; 105: 3679-3685.
72. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009; 16: 401-412.
73. Zirm E, Spies-Weisshart B, Heidel F, Schnetzke U, Bohmer FD, Hochhaus A et al. Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation. Br J Haematol 2012; 157: 483-492.
74. Moore AS, Blagg J, Linardopoulos S, Pearson AD. Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphiapositive leukemias. Leukemia 2010; 24: 671-678.
75. Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 2001; 98: 2301-2307.
76. Guzman ML, Rossi RM, Karnischky L, Li X, Peterson DR, Howard DS et al. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 2005; 105: 4163-4169.
77. Frelin C, Imbert V, Griessinger E, Peyron AC, Rochet N, Philip P et al. Targeting NF-kappaB activation via pharmacologic inhibition of IKK2-induced apoptosis of human acute myeloid leukemia cells. Blood 2005; 105: 804-811.
78. Griessinger E, Imbert V, Lagadec P, Gonthier N, Dubreuil P, Romanelli A et al. AS602868, a dual inhibitor of IKK2 and FLT3 to target AML cells. Leukemia 2007; 21: 877-885.
79. Fathi AT, Arowojolu O, Swinnen I, Sato T, Rajkhowa T, Small D et al. A potential therapeutic target for FLT3-ITD AML: PIM1 kinase. Leuk Res 2012; 36: 224-231.
80. Takahashi S, Harigae H, Yokoyama H, Ishikawa I, Abe S, Imaizumi M et al. Synergistic effect of arsenic trioxide and flt3 inhibition on cells with flt3 internal tandem duplication. Int J Hematol 2006; 84: 256-261.
81. Nishioka C, Ikezoe T, Yang J, Takeuchi S, Koeffler HP, Yokoyama A. MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein in AML cells. Leuk Res 2008; 32: 1382-1392.
82. Al Shaer L, Walsby E, Gilkes A, Tonks A, Walsh V, Mills K et al. Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling. Br J Haematol 2008; 141: 483-493.
83. Weisberg E, Liu Q, Nelson E, Kung AL, Christie AL, Bronson R et al. Using combination therapy to override stromal-mediated chemoresistance in mutant FLT3-positive AML: synergism between FLT3 inhibitors, dasatinib/multi-targeted inhibitors, and JAK inhibitors. Leukemia 2012; e-pub ahead of print 3 April 2012; doi:10.1038/leu.2012.96.
84. Knapper S, Burnett AK, Littlewood T, Kell WJ, Agrawal S, Chopra R et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood 2006; 108: 3262-3270.
85. Stone RM, DeAngelo DJ, Klimek V, Galinsky I, Estey E, Nimer SD et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood 2005; 105: 54-60.
86. Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A et al. Compassionate use of sorafenib in FLT3-ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood 2009; 113: 6567-6571.
87. Pratz KW, Cho E, Levis MJ, Karp JE, Gore SD, McDevitt M et al. A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias. Leukemia 2010; 24: 1437-1444.
88. Metzelder S, Schroeder T, Finck A, Scholl S, Fey M, Gotze K et al. High activity of sorafenib in FLT3-ITD-positive acute myeloid leukemia (AML) synergizes with allo-immune effects to induce sustained responses. Leukemia 2012; e-pub ahead of print 16 April 2012; doi:10.1038/leu.2012.105.
89. Giles FJ, Stopeck AT, Silverman LR, Lancet JE, Cooper MA, Hannah AL et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 2003; 102: 795-801.
90. Abu-Duhier FM, Goodeve AC, Wilson GA, Care RS, Peake IR, Reilly JT. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br J Haematol 2001; 113: 983-988.
91. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97: 2434-2439.
92. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326-4335.
93. Moreno I, Martin G, Bolufer P, Barragan E, Rueda E, Roman J et al. Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica 2003; 88: 19-24.
94. Andersson A, Johansson B, Lassen C, Mitelman F, Billstrom R, Fioretos T. Clinical impact of internal tandem duplications and activating point mutations in FLT3 in acute myeloid leukemia in elderly patients. Eur J Haematol 2004; 72: 307-313.
95. Auewarakul CU, Sritana N, Limwongse C, Thongnoppakhun W, Yenchitsomanus PT. Mutations of the FLT3 gene in adult acute myeloid leukemia: determination of incidence and identification of a novel mutation in a Thai population. Cancer Genet Cytogenet 2005; 162: 127-134.
96. Wang L, Lin D, Zhang X, Chen S, Wang M, Wang J. Analysis of FLT3 internal tandem duplication and D835 mutations in Chinese acute leukemia patients. Leuk Res 2005; 29: 1393-1398.
97. Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE. 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 2007; 110: 1262-1270.
98. Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S. Prognostic releVance of FLT3-TKD mutations in AML: the combination matters-an analysis of 3082 patients. Blood 2008; 111: 2527-2537.
99. Whitman SP, Ruppert AS, Radmacher MD, Mrozek K, Paschka P, Langer C et al. FLT3 D835/I836 mutations are associated with poor disease-free survival and a distinct gene-expression signature among younger adults with de novo cytogenetically normal acute myeloid leukemia lacking FLT3 internal tandem duplications. Blood 2008; 111: 1552-1559.
100. Weisberg E, Roesel J, Furet P, Bold G, Imbach P, Florsheimer A et al. Antileukemic effects of novel first-and second-generation flt3 inhibitors: structure-affinity comparison. Genes Cancer 2010; 1: 1021-1032.
101. Gozgit JM, Wong MJ, Wardwell S, Tyner JW, Loriaux MM, Mohemmad QK et al. Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther 2011; 10: 1028-1035.
102. Hernandez-Davies JE, Zape JP, Landaw EM, Tan X, Presnell A, Griffith D et al. The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3beta-dependent pathway. Mol Cancer Ther 2011; 10: 949-959.
103. Burkholder TP, Clayton JR, Rempala ME, Henry JR, Knobeloch JM, Mendel D et al. Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model. Invest New Drugs 2012; 30: 936-49.
104. Nordigarden A, Zetterblad J, Trinks C, Green H, Eliasson P, Druid P et al. Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice. Br J Haematol 2011; 155: 198-208.
105. Cao ZX, Liu JJ, Zheng RL, Yang J, Zhong L, Xu Y et al. SKLB1028, a novel oral multikinase inhibitor of EGFR, FLT3 and Abl, displays exceptional activity in models of FLT3-driven AML and considerable potency in models of CML harboring Abl mutants. Leukemia 2012; e-pub ahead of print 9 March 2012; doi:10.1038/leu.2012.67.
106. Li WW, Wang XY, Zheng RL, Yan HX, Cao ZX, Zhong L et al. Discovery of the novel potent and selective FLT3 inhibitor 1-{5-[7-(3-morpholinopropoxy) quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and its anti-acute myeloid leukemia (AML) activities in vitro and in vivo. J Med Chem 2012; 55: 3852-3866.
107. Lin WH, Jiaang WT, Chen CW, Yen KJ, Hsieh SY, Yen SC et al. BPR1J-097, a novel FLT3 kinase inhibitor, exerts potent inhibitory activity against AML. Br J Cancer 2012; 106: 475-481.
108. Davies RJ, Pierce AC, Forster C, Grey R, Xu J, Arnost M et al. Design, synthesis, and evaluation of a novel dual FMS-like tyrosine kinase 3/stem cell factor receptor (FLT3/c-KIT) inhibitor for the treatment of acute myelogenous leukemia. J Med Chem 2011; 54: 7184-7192.
109. Heidary DK, Huang G, Boucher D, Ma J, Forster C, Grey R et al. VX-322: a novel dual receptor tyrosine kinase inhibitor for the treatment of acute myelogenous leukemia. J Med Chem 2012; 55: 725-734.
110. Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 2004; 101: 3130-3135.
111. Ikezoe T, Nishioka C, Tasaka T, Yang Y, Komatsu N, Togitani K et al. The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol Cancer Ther 2006; 5: 2522-2530.
112. Nishioka C, Ikezoe T, Yang J, Takeshita A, Taniguchi A, Komatsu N et al. Blockade of MEK/ERK signaling enhances sunitinib-induced growth inhibition and apoptosis of leukemia cells possessing activating mutations of the FLT3 gene. Leuk Res 2008; 32: 865-872.
113. Weisberg E, Banerji L, Wright RD, Barrett R, Ray A, Moreno D et al. Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL-and mutant FLT3-expressing cells. Blood 2008; 111: 3723-3734.
114. Ahmad R, Liu S, Weisberg E, Nelson E, Galinsky I, Meyer C et al. Combining the FLT3 inhibitor PKC412 and the triterpenoid CDDO-Me synergistically induces apoptosis in acute myeloid leukemia with the internal tandem duplication mutation. Mol Cancer Res 2010; 8: 986-993.
115. Fathi AT, Arowojolu O, Swinnen I, Sato T, Rajkhowa T, Small D et al. A potential therapeutic target for FLT3-ITD AML: PIM1 kinase. Leuk Res 2012; 36: 224-231.
116. Zhou J, Bi C, Chng WJ, Cheong LL, Liu SC, Mahara S et al. PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-AML therapy. PLoS One 2011; 6: e19798.
117. Goh KC, Novotny-Diermayr V, Hart S, Ong LC, Loh YK, Cheong A et al. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent antileukemic properties. Leukemia 2012; 26: 236-243.
118. Lou YJ. Novel targeted therapy for acute myeloid leukemia with a dual FLT3 and JAK2 inhibitor. Acta Pharmacol Sin 2012; 33: 212-213.