Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Leukemia

Volumn 26, Issue 10, 2012, Pages 2176-2185

  Swords, R ^a   Freeman, C ^b   Giles, F ^c  

^a UNIVERSITY OF MIAMI   (United States)

^b ST BARTHOLOMEW S HOSPITAL   (United Kingdom)

^c TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

Acute myeloid leukemia; FLT3; Internal tandem duplication; Tyrosine kinase inhibitors

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; [4 [2 (1H INDAZOL 3 YL)VINYL]PHENYL](1 PIPERAZINYL)METHANONE; ARSENIC TRIOXIDE; AZACITIDINE; BORTEZOMIB; CD135 ANTIGEN; CHEMOKINE RECEPTOR CXCR4 ANTAGONIST; CYTARABINE; DAUNORUBICIN; EVEROLIMUS; FLT3 LIGAND; GRANULOCYTE COLONY STIMULATING FACTOR; HEAT SHOCK PROTEIN 90 INHIBITOR; IDARUBICIN; LESTAURTINIB; MIDOSTAURIN; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MONOCLONAL ANTIBODY; PLERIXAFOR; QUIZARTINIB; SORAFENIB; TANDUTINIB;

ACUTE GRANULOCYTIC LEUKEMIA; CANCER COMBINATION CHEMOTHERAPY; CANCER PATIENT; CANCER PROGNOSIS; CANCER RECURRENCE; CANCER RISK; CANCER SURVIVAL; CYTOGENETICS; DIARRHEA; DISEASE FREE SURVIVAL; DRUG EFFICACY; DRUG SAFETY; DYSPNEA; EVENT FREE SURVIVAL; FATIGUE; FEBRILE NEUTROPENIA; FEVER; GASTROINTESTINAL TOXICITY; GENE FUNCTION; GENE MUTATION; GENE STRUCTURE; GENETIC RISK; HUMAN; HYPERBILIRUBINEMIA; HYPERTENSION; HYPERTRANSAMINASEMIA; HYPOKALEMIA; IN VITRO STUDY; INTRACELLULAR SIGNALING; KIDNEY CARCINOMA; LEUKEMIA CELL; LEUKEMOGENESIS; LIVER CELL CARCINOMA; MOLECULARLY TARGETED THERAPY; MUCOSA INFLAMMATION; MUSCLE WEAKNESS; NEUTROPENIA; NONHUMAN; OVERALL SURVIVAL; PERIORBITAL EDEMA; PERIPHERAL EDEMA; PNEUMONIA; PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN STRUCTURE; QT PROLONGATION; RASH; REVIEW; SEPSIS; SIDE EFFECT; TASTE; UPREGULATION;

BENZENESULFONATES; BENZOTHIAZOLES; CARBAZOLES; CCAAT-ENHANCER-BINDING PROTEIN-ALPHA; FMS-LIKE TYROSINE KINASE 3; HUMANS; LEUKEMIA, MYELOID, ACUTE; MUTATION; PHENYLUREA COMPOUNDS; PROGNOSIS; PYRIDINES; STAUROSPORINE;

EID: 84867396974     PISSN: 08876924     EISSN: 14765551     Source Type: Journal    
DOI: 10.1038/leu.2012.114     Document Type: Review

References (118)

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277-300.
2. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116: 354-365.
3. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322-2333. (Pubitemid 28452973)
4. Fröhling S, Schlenk RF, Kayser S, Morhardt M, Benner A, Döhner K et al. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B. Blood 2006; 108: 3280-3288.
5. Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325-4336. (Pubitemid 35429670)
6. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075-4083.
7. Frohling S, Scholl C, Gilliland DG, Levine RL. Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 2005; 23: 6285-6295. (Pubitemid 46218838)
8. Mrozek K, Bloomfield CD. Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. Am Soc Hematol Educ Program 2006; 2006: 169-177.
9. Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 2007; 109: 431-448. (Pubitemid 46105936)
10. Kayser S, Schlenk RF, Londono MC, Breitenbuecher F, Wittke K, Du J et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 2009; 114: 2386-2392.
11. Schnittger S, Kinkelin U, Schoch C, Heinecke A, Haase D, Haferlach T et al. Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. Leukemia 2000; 14: 796-804. (Pubitemid 30235055)
12. Becker H, Marcucci G, Maharry K, Radmacher MD, Mrozek K, Margeson D et al. Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood 2010; 116: 788-792.
13. Baldus CD, Tanner SM, Ruppert AS, Whitman SP, Archer KJ, Marcucci G et al. BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study. Blood 2003; 102: 1613-1618. (Pubitemid 37022550)
14. Takahashi S. Current findings for recurring mutations in acute myeloid leukemia. J Hematol Oncol 2011; 4: 36.
15. Bienz M, Ludwig M, Leibundgut EO, Mueller BU, Ratschiller D, Solenthaler M et al. Risk assessment in patients with acute myeloid leukemia and a normal karyotype. Clin Cancer Res 2005; 11: 1416-1424. (Pubitemid 40315221)
16. Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 1996; 87: 1089-1096. (Pubitemid 26043536)
17. Rosnet O, Buhring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 1996; 10: 238-248. (Pubitemid 26102887)
18. Weisberg E, Barrett R, Liu Q, Stone R, Gray N, Griffin JD. FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug Resist Updat 2009; 12: 81-89.
19. Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998; 91: 1101-1134. (Pubitemid 28086863)
20. Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF et al. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 1994; 368: 643-648. (Pubitemid 24153389)
21. Small D, Levenstein M, Kim E, Carow C, Amin S, Rockwell P et al. STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc Natl Acad Sci USA 1994; 91: 459-463. (Pubitemid 24041421)
22. Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 1995; 3: 147-161.
23. McKenna HJ, Stocking KL, Miller RE, Brasel K, De Smedt T, Maraskovsky E et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000; 95: 3489-3497. (Pubitemid 30428482)
24. Kiyoi H, Ohno R, Ueda R, Saito H, Naoe T. Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene 2002; 21: 2555-2563. (Pubitemid 34438108)
25. 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. (Pubitemid 28442377)
26. Griffith J, Black J, Faerman C, Swenson L, Wynn M, Lu F et al. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 2004; 13: 169-178. (Pubitemid 38183264)
27. Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002; 99: 310-318.
28. Zheng R, Bailey E, Nguyen B, Yang X, Piloto O, Levis M et al. Further activation of FLT3 mutants by FLT3 ligand. Oncogene 2011; 30: 4004-4014.
29. 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. (Pubitemid 32634768)
30. 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. (Pubitemid 32291491)
31. 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.
32. 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.
33. 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. (Pubitemid 35434129)
34. 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. (Pubitemid 35177429)
35. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel 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. (Pubitemid 34627197)
36. Ravandi F, Kantarjian H, Faderl S, Garcia-Manero G, O'Brien S, Koller C et al. Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse. Leuk Res 2010; 34: 752-756.
37. Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009; 361: 1249-1259.
38. 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.
39. 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. (Pubitemid 36927159)
40. 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.
41. Schlenk RF, Dohner K, Krauter J, Frohling S, Corbacioglu A, Bullinger L et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358: 1909-1918. (Pubitemid 351620111)
42. 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. (Pubitemid 47281424)
43. Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli MF et al. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005; 106: 3733-3739. (Pubitemid 41739006)
44. Dohner K, Schlenk RF, Habdank M, Scholl C, Rucker FG, Corbacioglu A et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood 2005; 106: 3740-3746. (Pubitemid 41739007)
45. Preudhomme C, Sagot C, Boissel N, Cayuela JM, Tigaud I, de Botton S et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 2002; 100: 2717-2723.
46. Frohling S, Schlenk RF, Stolze I, Bihlmayr J, Benner A, Kreitmeier S et al. CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 2004; 22: 624-633. (Pubitemid 41095065)
47. Stirewalt DL, Kopecky KJ, Meshinchi S, Engel JH, Pogosova-Agadjanyan EL, Linsley J et al. Size of FLT3 internal tandem duplication has prognostic significance in patients with acute myeloid leukemia. Blood 2006; 107: 3724-3726.
48. Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res 2001; 61: 7233-7239. (Pubitemid 32946520)
49. Bornhäuser M, Illmer T, Schaich M, Soucek S, Ehninger G, Thiede C. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood 2007; 109: 2264-2265. (Pubitemid 46348234)
50. Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 2002; 1: 433-443. (Pubitemid 41039124)
51. Propper DJ, McDonald AC, Man A, Thavasu P, Balkwill F, Braybrooke JP et al. Phase I and Pharmacokinetic Study of PKC412, an Inhibitor of Protein Kinase C. J Clin Oncol 2001; 19: 1485-1492. (Pubitemid 32202557)
52. 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. (Pubitemid 40053063)
53. 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.
54. Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G et al. A Phase 1b study of midostaurin (PKC412) in combination with daunorubicin and cytarabine induction and high-dose cytarabine consolidation in patients under age 61 with newly diagnosed de novo acute myeloid leukemia: overall survival of patients whose blasts have FLT3 mutations is similar to those with wild-type FLT3. Blood 2009; 114: 263.
55. Stone RM, Dohner H, Ehninger G, Villeneuve M, Teasdale T, Virkus JD et al. CALGB 10603 (RATIFY): a randomized phase III study of induction (daunorubicin/cytarabine) and consolidation (high-dose cytarabine) chemotherapy combined with midostaurin or placebo in treatment-naive patients with FLT3 mutated AML. J Clin Oncol 2011; 29: 31s.
56. 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.
57. Hexner EO, Serdikoff C, Jan M, Swider CR, Robinson C, Yang S et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood 2008; 111: 5663-5671.
58. 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. (Pubitemid 38596280)
59. Levis M, Pham R, Smith BD, Small D. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood 2004; 104: 1145-1150. (Pubitemid 39038036)
60. 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.
61. 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.
62. Knapper S, Burnett AK, Hills RK, Small D, Levis M. Lestaurtinib FLT3 inhibitory activity is modulated by concomitant azole therapy and may influence relapse risk. Blood 2009; 114: 326.
63. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099-7109. (Pubitemid 39331023)
64. 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.
65. Lee SH, Paietta E, Racevskis J, Wiernik PH. Complete resolution of leukemia cutis with sorafenib in an acute myeloid leukemia patient with FLT3-ITD mutation. Am J Hematol 2009; 84: 701-702.
66. Safaian NN, Czibere A, Bruns I, Fenk R, Reinecke P, Dienst A et al. Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3-ITD+ acute myeloid leukemia. Leuk Res 2009; 33: 348-350.
67. 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.
68. 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.
69. Serve H, Wagner R, Sauerland C, Brunnberg U, Krug U, Schaich M et al. Sorafenib in combination with standard induction and consolidation therapy in elderly AML patients: results from a randomized, placebo-controlled phase II trial. Blood 2010; 116: 151.
70. Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009; 114: 2984-2992.
71. Kampa-Schittenhelm KM, Trikha M, Schlenk RF, Doehner H, Doehner K, Heinrich MC et al. AC220, a potent second generation class I/III tyrosine kinase inhibitor, displays a distinct inhibition profile on mutant-FLT3 as well as -KIT isoforms. Blood 2010; 116: 132.
72. James J, Pratz K, Stine A, Apuy JL, Insko DE, Armstrong RC et al. Clinical pharmacokinetics and FLT3 phosphorylation of AC220, a highly potent and selective inhibitor of FLT3. Blood 2008; 112: 912.
73. Trikha M, Cortes J, Foran J, Ghirdaladze D, DeVetten M, Zodelava M et al. AC220, a potent, selective, second-generation FLT3 receptor tyrosine kinase inhibitor in a first-in-human phase 1 AML study. Haematologica 2010; 96: 460-461.
74. Cortes J, Perl A, Smith C, Kovacsovics T, Dombret H, Döhner H et al. A phase II open-label, AC220 monotherapy efficacy (ACE) study in patients with acute myeloid leukemia (AML) with FLT3-ITD activating mutations: Interim results. Haematologica 2011; 96: 426.
75. Kelly LM, Yu JC, Boulton CL, Apatira M, Li J, Sullivan CM et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell 2002; 1: 421-432. (Pubitemid 41039123)
76. 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. (Pubitemid 44864544)
77. Schittenhelm MM, Kampa KM, Yee KW, Heinrich MC. The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin. Cell Cycle 2009; 8: 2621-2630.
78. Pratz KW, Sato T, Murphy KM, Stine A, Rajkhowa T, Levis M. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML. Blood 2010; 115: 1425-1432.
79. Kottaridis PD, Gale RE, Langabeer SE, Frew ME, Bowen DT, Linch DC. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 2002; 100: 2393-2398.
80. 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.
81. 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.
82. 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.
83. Cools J, Mentens N, Furet P, Fabbro D, Clark JJ, Griffin JD et al. Prediction of resistance to small molecule FLT3 inhibitors. Cancer Res 2004; 64: 6385-6389.
84. Lyman SD, Seaberg M, Hanna R, Zappone J, Brasel K, Abkowitz JL et al. Plasma/serum levels of flt3 ligand are low in normal individuals and highly elevated in patients with Fanconi anemia and acquired aplastic anemia. Blood 1995; 86: 4091-4096.
85. Wodnar-Filipowicz A, Lyman SD, Gratwohl A, Tichelli A, Speck B, Nissen C. Flt3 ligand level reflects hematopoietic progenitor cell function in aplastic anemia and chemotherapy-induced bone marrow aplasia. Blood 1996; 88: 4493-4499. (Pubitemid 26419132)
86. Bojko P, Pawloski D, Stellberg W, Schroder JK, Seeber S. Flt3 ligand and thrombopoietin serum levels during peripheral blood stem cell mobilization with chemotherapy and recombinant human glycosylated granulocyte colonystimulating factor (rhu-G-CSF, lenograstim) and after high-dose chemotherapy. Ann Hematol 2002; 81: 522-528. (Pubitemid 36075505)
87. Youssoufian H, Rowinsky EK, Tonra J, Li Y, Targeting FMS. related tyrosine kinase receptor 3 with the human immunoglobulin G1 monoclonal antibody IMC-EB10. Cancer 2010; 116: 1013-1017.
88. Bagrintseva K, Schwab R, Kohl TM, Schnittger S, Eichenlaub S, Ellwart JW et al. Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells. Blood 2004; 103: 2266-2275. (Pubitemid 38326246)
89. Li Y, Zhu Z. Monoclonal antibody-based therapeutics for leukemia. Expert Opin Biol Ther 2007; 7: 319-330. (Pubitemid 46383475)
90. Li Y, Zhu Z. FLT3 antibody-based therapeutics for leukemia therapy. Int J Hematol 2005; 82: 108-114. (Pubitemid 41233168)
91. Williams B, Atkins A, Zhang H, Lu D, Jimenez X, Li H et al. Cell-based selection of internalizing fully human antagonistic antibodies directed against FLT3 for suppression of leukemia cell growth. Leukemia 2005; 19: 1432-1438. (Pubitemid 41136338)
92. Li Y, Li H, Wang MN, Lu D, Bassi R, Wu Y et al. Suppression of leukemia expressing wild-type or ITD-mutant FLT3 receptor by a fully human anti-FLT3 neutralizing antibody. Blood 2004; 104: 1137-1144. (Pubitemid 39038035)
93. Piloto O, Levis M, Huso D, Li Y, Li H, Wang MN et al. Inhibitory anti-FLT3 antibodies are capable of mediating antibody-dependent cell-mediated cytotoxicity and reducing engraftment of acute myelogenous leukemia blasts in nonobese diabetic/severe combined immunodeficient mice. Cancer Res 2005; 65: 1514-1522. (Pubitemid 40276832)
94. Piloto O, Wright M, Brown P, Kim KT, Levis M, Small D. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways. Blood 2007; 109: 1643-1652. (Pubitemid 46239599)
95. Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 2003; 21: 778-784. (Pubitemid 36791396)
96. Ju S, Xue Z, Ju S, Ge Y, Xie W, Zhu H et al. Anti-human FLT3 monoclonal antibody that inhibits proliferation of monocytic leukemia cell line SHI-1. Hybridoma (Larchmt) 2011; 30: 61-67.
97. Hofmann M, Grosse-Hovest L, Nubling T, Pyz E, Bamberg ML, Aulwurm S et al. Generation, selection and preclinical characterization of an Fc-optimized FLT3 antibody for the treatment of myeloid leukemia. Leukemia 2012; e-pub ahead of print 6 January 2012; doi:10.1038/leu.2011.372.
98. Yee KW, Schittenhelm M, O'Farrell AM, Town AR, McGreevey L, Bainbridge T et al. Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITDpositive leukemic cells. Blood 2004; 104: 4202-4209. (Pubitemid 39620175)
99. Pratz K, Levis M. Incorporating FLT3 inhibitors into acute myeloid leukemia treatment regimens. Leuk Lymphoma 2008; 49: 852-863. (Pubitemid 351942737)
100. Fukuda S, Broxmeyer HE, Pelus LM. Flt3 ligand and the Flt3 receptor regulate hematopoietic cell migration by modulating the SDF-1a (CXCL12)/CXCR4 axis. Blood 2005; 105: 3117-3126.
101. Tavor S, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res 2004; 64: 2817-2824. (Pubitemid 38500620)
102. Rombouts EJC, Pavic B, Löwenberg B, Ploemacher RE. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004; 104: 550-557. (Pubitemid 38900040)
103. Nervi B, Ramirez P, Rettig MP, Uy GL, Holt MS, Ritchey JK et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood 2009; 113: 6206-6214.
104. Juarez J, Dela Pena A, Baraz R, Hewson J, Khoo M, Cisterne A et al. CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia 2007; 21: 1249-1257. (Pubitemid 46831814)
105. Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, Frolova O et al. Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 2009; 113: 6215-6224.
106. Miranda MB, McGuire TF, Johnson DE. Importance of MEK-1/-2 signaling in monocytic and granulocytic differentiation of myeloid cell lines. Leukemia 2002; 16: 683-692. (Pubitemid 34449751)
107. Takahashi S. Inhibition of the MEK/MAPK signal transduction pathway strongly impairs the growth of Flt3-ITD cells. Am J Hematol 2006; 81: 154-155. (Pubitemid 43208619)
108. Milella M, Kornblau SM, Estrov Z, Carter BZ, Lapillonne H, Harris D et al. Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. J Clin Invest 2001; 108: 851-859. (Pubitemid 32880294)
109. Radomska HS, Basseres DS, Zheng R, Zhang P, Dayaram T, Yamamoto Y et al. Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations. J Exp Med 2006; 203: 371-381. (Pubitemid 43290846)
110. Lunghi P, Costanzo A, Salvatore L, Noguera N, Mazzera L, Tabilio A et al. MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxideinduced apoptosis. Blood 2006; 107: 4549-4553. (Pubitemid 43801384)
111. 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. (Pubitemid 44619248)
112. Douer D, Tallman MS. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol 2005; 23: 2396-2410. (Pubitemid 46218734)
113. Minami Y, Kiyoi H, Yamamoto Y, Yamamoto K, Ueda R, Saito H et al. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 2002; 16: 1535-1540.
114. Yao Q, Nishiuchi R, Li Q, Kumar AR, Hudson WA, Kersey JH. FLT3 expressing leukemias are selectively sensitive to inhibitors of the molecular chaperone heat shock protein 90 through destabilization of signal transduction-associated kinases. Clin Cancer Res 2003; 9: 4483-4493. (Pubitemid 37248407)
115. George P, Bali P, Cohen P, Tao J, Guo F, Sigua C et al. Cotreatment with 17- allylamino-demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res 2004; 64: 3645-3652. (Pubitemid 38657944)
116. Yao Q, Nishiuchi R, Kitamura T, Kersey JH. Human leukemias with mutated FLT3 kinase are synergistically sensitive to FLT3 and Hsp90 inhibitors: the key role of the STAT5 signal transduction pathway. Leukemia 2005; 19: 1605-1612. (Pubitemid 43090405)
117. Caligiuri MA, Strout MP, Lawrence D, Arthur DC, Baer MR, Yu F et al. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res 1998; 58: 55-59. (Pubitemid 28027716)
118. Munoz L, Nomdedeu JF, Villamor N, Guardia R, Colomer D, Ribera JM et al. Acute myeloid leukemia with MLL rearrangements: clinicobiological features, prognostic impact and value of flow cytometry in the detection of residual leukemic cells. Leukemia 2003; 17: 76-82. (Pubitemid 36175891)