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Gene Review

FLT3  -  fms-related tyrosine kinase 3

Homo sapiens

Synonyms: CD135, FL cytokine receptor, FLK-2, FLK2, FLT-3, ...
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Disease relevance of FLT3


High impact information on FLT3

  • These studies demonstrate the importance of the Flt3 receptor tyrosine kinase as the earliest marker of hematopoietic cell fate commitment in that erythrocyte and megakaryocyte potentials are lost first as HSCs differentiate to lymphocyte progenitors [7].
  • The FLT3/FLK2 receptor tyrosine kinase is closely related to two receptors, c-Kit and c-Fms, which function with their respective ligands, Kit ligand and macrophage colony-stimulating factor to control differentiation of haematopoietic and non-haematopoietic cells [8].
  • Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs [8].
  • We have purified to homogeneity and partially sequenced a soluble form of the FLT3/FLK2 ligand produced by mouse thymic stromal cells [8].
  • Repression of Flt3 by Pax5 is crucial for B-cell lineage commitment [9].

Chemical compound and disease context of FLT3


Biological context of FLT3

  • FLT3 is a type III receptor tyrosine kinase that is thought to play a key role in hematopoiesis [1].
  • FLT3 is constitutively activated either by an internal tandem duplication (ITD) or by a point mutation (PM) in 17% to 24% of pediatric AML cases [14].
  • SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro [15].
  • FLT3/ITD-positive patients were significantly older and had higher percentages of normal cytogenetic findings or French-American-British (FAB) classification M1/M2 and lower percentages of 11q23 abnormalities or FAB M5 [16].
  • Introduction of these dual ITD-TKD, but not single D835N or Y842H FLT3 mutants, in Ba/F3 cells restored the FLT3 inhibitor resistant phenotype [17].

Anatomical context of FLT3

  • Activating mutations in FLT3, including internal tandem duplication (ITD) in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth [18].
  • Internal tandem duplications of the FLT3 gene are present in leukemia stem cells [19].
  • We determined the antileukemic activity of CEP-701, a potent and selective FLT3 inhibitor, in 8 ALL cell lines and 39 bone marrow samples obtained at diagnosis from infants and children with various subtypes of ALL [20].
  • Both mutations were associated with higher white blood cell (WBC) count at presentation; 75% of the patients with WBC counts of 10 x 10(9)/L or greater had mutant FLT3 [21].
  • FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells [16].

Associations of FLT3 with chemical compounds

  • SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo [15].
  • SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3 [22].
  • The Expand Long Template PCR System was used to determine the allelic location of internal tandem duplication of FLT3 (FLT3/ITD) and Asp(835) mutations [23].
  • The current study evaluated the single and combined effects of 17-AAG and GTP14564, and the role of FLT3 in their inhibitory effects [11].
  • Complete remission was observed following treatment with daunorubicin and cytosine arabinoside, but after 37 months the patient relapsed with t-AML of subtype M3 with a t(15;17) and the same FLT3/ITD was still present [24].
  • The potency of Sunitinib against FLT3 K663Q was similar to its potency against FLT3 ITD mutations [25].

Physical interactions of FLT3

  • We found that activation of FLT3 in human AML inhibits CCAAT/enhancer binding protein alpha (C/EBPalpha) function by ERK1/2-mediated phosphorylation, which may explain the differentiation block of leukemic blasts [26].
  • JNK1 co-immunoprecipitated from such lysates with p85-cbl-crkII/L and bound to Crk species SH3 domain in pull-down assay. siRNA-mediated depletion of Flt3 or of cbl, the adaptor at the nexus of this signaling group, inhibited JNK activity on substrate c-jun [27].
  • Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2 [28].
  • A chimeric cytokine, progenipoietin-1 (ProGP-1), containing the G-CSF and FL receptor agonists binds both the G-CSF receptor and FLT-3 [29].

Enzymatic interactions of FLT3


Regulatory relationships of FLT3

  • In addition, SU11248 inhibits FLT3-induced VEGF production [15].
  • In some cases, FLT3 was expressed at levels equivalent to GAPDH in the absence of genomic amplification [31].
  • Autocrine stimulation of wild-type (WT) FLT3 by coexpressed FLT3 ligand (FL) occurs in many other cases [14].
  • In this study, we examined the possible role of SHP-1 in regulating FLT3 signaling [32].
  • These observations suggest that reduced AML1 activities predispose cells to the acquisition of the activating FLT3 mutation as a secondary event leading to full transformation in AML M0 [33].

Other interactions of FLT3

  • NPM1 mutations were associated with normal karyotype and with internal tandem duplication (ITD) and D835 mutations in FLT3, but not with other mutations [34].
  • We studied 203 patients with PML-RARA-positive APL; 43% of the patients had an FLT3 mutation (65 internal tandem duplications [ITDs], 19 D835/I836, 4 ITD+D835/I836) [21].
  • Gene expression scores of FLT3, MeisI, and CD44 for samples with MLL rearrangements were particularly high compared with those for other ALL samples [35].
  • In acute myeloid leukemia (AML), constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplications (FLT3-ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (FLT3-TKD), as well as point mutations of the NRAS gene (NRAS-PM) are among the most frequent somatic gene mutations [36].
  • Further analyses of 23 of these cases uncovered one FLT3 internal tandem duplication and five TP53 mutations [37].

Analytical, diagnostic and therapeutic context of FLT3

  • Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations [38].
  • Our results indicate the need for clinical trials to test the efficacy of drugs that inhibit the FLT3 RTK in this subset of patients with T-ALL [39].
  • To determine if FLT3 protein was also overexpressed, proteins were extracted from leukemic BM samples and screened by Western blotting with anti-FLT3 antisera [40].
  • Primary AML blasts bearing FLT3-Y842C mutations showed constitutive FLT3 and signal transducer and activator of transcription 5 (STAT-5) tyrosine phosphorylation [41].
  • FLT3/ITD-positive patients had lower remission induction rates (70% vs 88%; P =.01) and lower 5-year probability rates of event-free survival (pEF) (29% vs 46%; P =.0046) and overall survival (32% vs 58%; P =.037) [16].


  1. The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Griffith, J., Black, J., Faerman, C., Swenson, L., Wynn, M., Lu, F., Lippke, J., Saxena, K. Mol. Cell (2004) [Pubmed]
  2. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Ozeki, K., Kiyoi, H., Hirose, Y., Iwai, M., Ninomiya, M., Kodera, Y., Miyawaki, S., Kuriyama, K., Shimazaki, C., Akiyama, H., Nishimura, M., Motoji, T., Shinagawa, K., Takeshita, A., Ueda, R., Ohno, R., Emi, N., Naoe, T. Blood (2004) [Pubmed]
  3. FLT3 mutations in childhood acute lymphoblastic leukemia. Armstrong, S.A., Mabon, M.E., Silverman, L.B., Li, A., Gribben, J.G., Fox, E.A., Sallan, S.E., Korsmeyer, S.J. Blood (2004) [Pubmed]
  4. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Zheng, R., Levis, M., Piloto, O., Brown, P., Baldwin, B.R., Gorin, N.C., Beran, M., Zhu, Z., Ludwig, D., Hicklin, D., Witte, L., Li, Y., Small, D. Blood (2004) [Pubmed]
  5. 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. Kottaridis, P.D., Gale, R.E., Langabeer, S.E., Frew, M.E., Bowen, D.T., Linch, D.C. Blood (2002) [Pubmed]
  6. Structural and functional alterations of FLT3 in acute myeloid leukemia. Meshinchi, S., Appelbaum, F.R. Clin. Cancer Res. (2009) [Pubmed]
  7. The complex cartography of stem cell commitment. Akashi, K., Traver, D., Zon, L.I. Cell (2005) [Pubmed]
  8. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Hannum, C., Culpepper, J., Campbell, D., McClanahan, T., Zurawski, S., Bazan, J.F., Kastelein, R., Hudak, S., Wagner, J., Mattson, J. Nature (1994) [Pubmed]
  9. Repression of Flt3 by Pax5 is crucial for B-cell lineage commitment. Holmes, M.L., Carotta, S., Corcoran, L.M., Nutt, S.L. Genes Dev. (2006) [Pubmed]
  10. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. O'Farrell, A.M., Foran, J.M., Fiedler, W., Serve, H., Paquette, R.L., Cooper, M.A., Yuen, H.A., Louie, S.G., Kim, H., Nicholas, S., Heinrich, M.C., Berdel, W.E., Bello, C., Jacobs, M., Scigalla, P., Manning, W.C., Kelsey, S., Cherrington, J.M. Clin. Cancer Res. (2003) [Pubmed]
  11. Human leukemias with mutated FLT3 kinase are synergistically sensitive to FLT3 and Hsp90 inhibitors: the key role of the STAT5 signal transduction pathway. Yao, Q., Nishiuchi, R., Kitamura, T., Kersey, J.H. Leukemia (2005) [Pubmed]
  12. Establishment of a Stroma-Dependent Human Acute Myelomonocytic Leukemia Cell Line, NAMO-2, with FLT3 Tandem Duplication. Abe, A., Kiyoi, H., Ninomiya, M., Yamazaki, T., Murase, T., Ozeki, K., Suzuki, M., Hayakawa, F., Katsumi, A., Emi, N., Naoe, T. Int. J. Hematol. (2006) [Pubmed]
  13. 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. Deangelo, D.J., Stone, R.M., Heaney, M.L., Nimer, S.D., Paquette, R.L., Klisovic, R.B., Caligiuri, M.A., Cooper, M.R., Lecerf, J.M., Karol, M.D., Sheng, S., Holford, N., Curtin, P.T., Druker, B.J., Heinrich, M.C. Blood (2006) [Pubmed]
  14. Pediatric AML primary samples with FLT3/ITD mutations are preferentially killed by FLT3 inhibition. Brown, P., Meshinchi, S., Levis, M., Alonzo, T.A., Gerbing, R., Lange, B., Arceci, R., Small, D. Blood (2004) [Pubmed]
  15. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. O'Farrell, A.M., Abrams, T.J., Yuen, H.A., Ngai, T.J., Louie, S.G., Yee, K.W., Wong, L.M., Hong, W., Lee, L.B., Town, A., Smolich, B.D., Manning, W.C., Murray, L.J., Heinrich, M.C., Cherrington, J.M. Blood (2003) [Pubmed]
  16. FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance. Zwaan, C.M., Meshinchi, S., Radich, J.P., Veerman, A.J., Huismans, D.R., Munske, L., Podleschny, M., Hählen, K., Pieters, R., Zimmermann, M., Reinhardt, D., Harbott, J., Creutzig, U., Kaspers, G.J., Griesinger, F. Blood (2003) [Pubmed]
  17. 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. Bagrintseva, K., Schwab, R., Kohl, T.M., Schnittger, S., Eichenlaub, S., Ellwart, J.W., Hiddemann, W., Spiekermann, K. Blood (2004) [Pubmed]
  18. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Kelly, L.M., Kutok, J.L., Williams, I.R., Boulton, C.L., Amaral, S.M., Curley, D.P., Ley, T.J., Gilliland, D.G. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  19. Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Levis, M., Murphy, K.M., Pham, R., Kim, K.T., Stine, A., Li, L., McNiece, I., Smith, B.D., Small, D. Blood (2005) [Pubmed]
  20. FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Brown, P., Levis, M., Shurtleff, S., Campana, D., Downing, J., Small, D. Blood (2005) [Pubmed]
  21. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Gale, R.E., Hills, R., Pizzey, A.R., Kottaridis, P.D., Swirsky, D., Gilkes, A.F., Nugent, E., Mills, K.I., Wheatley, K., Solomon, E., Burnett, A.K., Linch, D.C., Grimwade, D. Blood (2005) [Pubmed]
  22. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Giles, F.J., Stopeck, A.T., Silverman, L.R., Lancet, J.E., Cooper, M.A., Hannah, A.L., Cherrington, J.M., O'Farrell, A.M., Yuen, H.A., Louie, S.G., Hong, W., Cortes, J.E., Verstovsek, S., Albitar, M., O'Brien, S.M., Kantarjian, H.M., Karp, J.E. Blood (2003) [Pubmed]
  23. Heterogeneous patterns of FLT3 Asp(835) mutations in relapsed de novo acute myeloid leukemia: a comparative analysis of 120 paired diagnostic and relapse bone marrow samples. Shih, L.Y., Huang, C.F., Wu, J.H., Wang, P.N., Lin, T.L., Dunn, P., Chou, M.C., Kuo, M.C., Tang, C.C. Clin. Cancer Res. (2004) [Pubmed]
  24. Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy. Christiansen, D.H., Pedersen-Bjergaard, J. Leukemia (2001) [Pubmed]
  25. FLT3 K663Q is a novel AML-associated oncogenic kinase: Determination of biochemical properties and sensitivity to Sunitinib (SU11248). Schittenhelm, M.M., Yee, K.W., Tyner, J.W., McGreevey, L., Haley, A.D., Town, A., Griffith, D.J., Bainbridge, T., Braziel, R.M., O'Farrell, A.M., Cherrington, J.M., Heinrich, M.C. Leukemia (2006) [Pubmed]
  26. Block of C/EBP alpha function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations. Radomska, H.S., Bassères, D.S., Zheng, R., Zhang, P., Dayaram, T., Yamamoto, Y., Sternberg, D.W., Lokker, N., Giese, N.A., Bohlander, S.K., Schnittger, S., Delmotte, M.H., Davis, R.J., Small, D., Hiddemann, W., Gilliland, D.G., Tenen, D.G. J. Exp. Med. (2006) [Pubmed]
  27. Constitutive c-jun N-terminal kinase activity in acute myeloid leukemia derives from Flt3 and affects survival and proliferation. Hartman, A.D., Wilson-Weekes, A., Suvannasankha, A., Burgess, G.S., Phillips, C.A., Hincher, K.J., Cripe, L.D., Boswell, H.S. Exp. Hematol. (2006) [Pubmed]
  28. Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2. Heiss, E., Masson, K., Sundberg, C., Pedersen, M., Sun, J., Bengtsson, S., Rönnstrand, L. Blood (2006) [Pubmed]
  29. Enhanced ability of the progenipoietin-1 to suppress apoptosis in human hematopoietic cells. Saleh, O.A., Blalock, W.L., Burrows, C., Steelman, L.S., Doshi, P.D., McKearn, J.P., McCubrey, J.A. Int. J. Mol. Med. (2002) [Pubmed]
  30. Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Tse, K.F., Allebach, J., Levis, M., Smith, B.D., Bohmer, F.D., Small, D. Leukemia (2002) [Pubmed]
  31. Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics. Roche, J., Zeng, C., Barón, A., Gadgil, S., Gemmill, R.M., Tigaud, I., Thomas, X., Drabkin, H.A. Leukemia (2004) [Pubmed]
  32. FLT3/ITD mutation signaling includes suppression of SHP-1. Chen, P., Levis, M., Brown, P., Kim, K.T., Allebach, J., Small, D. J. Biol. Chem. (2005) [Pubmed]
  33. Dual mutations in the AML1 and FLT3 genes are associated with leukemogenesis in acute myeloblastic leukemia of the M0 subtype. Matsuno, N., Osato, M., Yamashita, N., Yanagida, M., Nanri, T., Fukushima, T., Motoji, T., Kusumoto, S., Towatari, M., Suzuki, R., Naoe, T., Nishii, K., Shigesada, K., Ohno, R., Mitsuya, H., Ito, Y., Asou, N. Leukemia (2003) [Pubmed]
  34. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Suzuki, T., Kiyoi, H., Ozeki, K., Tomita, A., Yamaji, S., Suzuki, R., Kodera, Y., Miyawaki, S., Asou, N., Kuriyama, K., Yagasaki, F., Shimazaki, C., Akiyama, H., Nishimura, M., Motoji, T., Shinagawa, K., Takeshita, A., Ueda, R., Kinoshita, T., Emi, N., Naoe, T. Blood (2005) [Pubmed]
  35. Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearrangements. Tsutsumi, S., Taketani, T., Nishimura, K., Ge, X., Taki, T., Sugita, K., Ishii, E., Hanada, R., Ohki, M., Aburatani, H., Hayashi, Y. Cancer Res. (2003) [Pubmed]
  36. Distinct gene expression patterns associated with FLT3- and NRAS-activating mutations in acute myeloid leukemia with normal karyotype. Neben, K., Schnittger, S., Brors, B., Tews, B., Kokocinski, F., Haferlach, T., Müller, J., Hahn, M., Hiddemann, W., Eils, R., Lichter, P., Schoch, C. Oncogene (2005) [Pubmed]
  37. RAS, FLT3, and TP53 mutations in therapy-related myeloid malignancies with abnormalities of chromosomes 5 and 7. Side, L.E., Curtiss, N.P., Teel, K., Kratz, C., Wang, P.W., Larson, R.A., Le Beau, M.M., Shannon, K.M. Genes Chromosomes Cancer (2004) [Pubmed]
  38. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Thiede, C., Steudel, C., Mohr, B., Schaich, M., Schäkel, U., Platzbecker, U., Wermke, M., Bornhäuser, M., Ritter, M., Neubauer, A., Ehninger, G., Illmer, T. Blood (2002) [Pubmed]
  39. Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Paietta, E., Ferrando, A.A., Neuberg, D., Bennett, J.M., Racevskis, J., Lazarus, H., Dewald, G., Rowe, J.M., Wiernik, P.H., Tallman, M.S., Look, A.T. Blood (2004) [Pubmed]
  40. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Carow, C.E., Levenstein, M., Kaufmann, S.H., Chen, J., Amin, S., Rockwell, P., Witte, L., Borowitz, M.J., Civin, C.I., Small, D. Blood (1996) [Pubmed]
  41. Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML). Kindler, T., Breitenbuecher, F., Kasper, S., Estey, E., Giles, F., Feldman, E., Ehninger, G., Schiller, G., Klimek, V., Nimer, S.D., Gratwohl, A., Choudhary, C.R., Mueller-Tidow, C., Serve, H., Gschaidmeier, H., Cohen, P.S., Huber, C., Fischer, T. Blood (2005) [Pubmed]
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