The role of FLT3 in haematopoietic malignancies (original) (raw)

• Matthews, W., Jordan, C. T., Wiegand, G. W., Pardoll, D. & Lemischka, I. R. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 65, 1143–1152 (1991).
  CAS PubMed Google Scholar
• Rosnet, O., Marchetto, S., deLapeyriere, O. & Birnbaum, D. Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 6, 1641–1650 (1991). References 1 and 2 describe the initial cloning and expression of the mouse Fms-like tyrosine kinase 3 ( Flt3 ) gene.
  CAS PubMed Google Scholar
• Rosnet, O. et al. Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. Blood 82, 1110–1119 (1993).
  CAS PubMed Google Scholar
• Small, D. 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 91, 459–463 (1994). References 3 and 4 describe the initial cloning and expression of the human FLT3 gene.
  CAS PubMed PubMed Central Google Scholar
• Rosnet, O. et al. Close physical linkage of the FLT1 and FLT3 genes on chromosome 13 in man and chromosome 5 in mouse. Oncogene 8, 173–179 (1993).
  CAS PubMed Google Scholar
• Agnes, F. et al. Genomic structure of the downstream part of the human FLT3 gene: exon/intron structure conservation among genes encoding receptor tyrosine kinases (RTK) of subclass III. Gene 145, 283–288 (1994).
  CAS PubMed Google Scholar
• Rosnet, O. & Birnbaum, D. Hematopoietic receptors of class III receptor-type tyrosine kinases. Crit. Rev. Oncog. 4, 595–613 (1993).
  CAS PubMed Google Scholar
• Abu-Duhier, F. M. et al. Genomic structure of human FLT3: implications for mutational analysis. Br. J. Haematol. 113, 1076–1077 (2001). References 6 and 8 discuss the exon and intron structure of FLT3 , comparing FLT3 with other members of the receptor tyrosine kinase subclass III family.
  CAS PubMed Google Scholar
• Lyman, S. D. et al. Characterization of the protein encoded by the flt3 (flk2) receptor-like tyrosine kinase gene. Oncogene 8, 815–822 (1993).
  CAS PubMed Google Scholar
• Carow, C. E. et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood 87, 1089–1096 (1996).
  CAS PubMed Google Scholar
• Rosnet, O. et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia 10, 238–248 (1996).
  CAS PubMed Google Scholar
• Gabbianelli, M. et al. Multi-level effects of flt3 ligand on human hematopoiesis: expansion of putative stem cells and proliferation of granulomonocytic progenitors/monocytic precursors. Blood 86, 1661–1670 (1995).
  CAS PubMed Google Scholar
• Ratajczak, M. Z. et al. FLT3/FLK-2 (STK-1) ligand does not stimulate human megakaryopoiesis in vitro. Stem Cells 14, 146–150 (1996).
  CAS PubMed Google Scholar
• Hjertson, M., Sundstrom, C., Lyman, S. D., Nilsson, K. & Nilsson, G. Stem cell factor, but not flt3 ligand, induces differentiation and activation of human mast cells. Exp. Hematol. 24, 748–754 (1996).
  CAS PubMed Google Scholar
• Lyman, S. D. & Jacobsen, S. E. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 91, 1101–1134 (1998). An excellent review that outlines the cloning, structure, biology and possible clinical implications of FLT3 ligand (FLT3L). Comparisons between FLT3L and KIT ligand are made, which help to further characterize the importance of FLT3L.
  CAS PubMed Google Scholar
• Sabbath, K. D., Ball, E. D., Larcom, P., Davis, R. B. & Griffin, J. D. Heterogeneity of clonogenic cells in acute myeloblastic leukemia. J. Clin. Invest. 75, 746–753 (1985).
  CAS PubMed PubMed Central Google Scholar
• Nadler, L. M. et al. B cell origin of non-T cell acute lymphoblastic leukemia. A model for discrete stages of neoplastic and normal pre-B cell differentiation. J. Clin. Invest. 74, 332–340 (1984).
  CAS PubMed PubMed Central Google Scholar
• Rubartelli, A., Sitia, R., Zicca, A., Grossi, C. E. & Ferrarini, M. Differentiation of chronic lymphocytic leukemia cells: correlation between the synthesis and secretion of immunoglobulins and the ultrastructure of the malignant cells. Blood 62, 495–504 (1983).
  CAS PubMed Google Scholar
• Martin, P. J. et al. Involvement of the B-lymphoid system in chronic myelogenous leukaemia. Nature 287, 49–50 (1980).
  CAS PubMed Google Scholar
• Uckun, F. M. et al. Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study. J. Clin. Oncol. 15, 2214–2221 (1997).
  CAS PubMed Google Scholar
• Armstrong, S. A. et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genet. 30, 41–47 (2002).
  CAS PubMed Google Scholar
• Lyman, S. D. et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 75, 1157–1167 (1993).
  CAS PubMed Google Scholar
• Hannum, C. et al. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 368, 643–648 (1994).
  CAS PubMed Google Scholar
• Lyman, S. D. et al. Cloning of the human homologue of the murine flt3 ligand: a growth factor for early hematopoietic progenitor cells. Blood 83, 2795–2801 (1994).
  CAS PubMed Google Scholar
• Lyman, S. D. et al. Structural analysis of human and murine flt3 ligand genomic loci. Oncogene 11, 1165–1172 (1995).
  CAS PubMed Google Scholar
• Lyman, S. D. et al. Identification of soluble and membrane-bound isoforms of the murine flt3 ligand generated by alternative splicing of mRNAs. Oncogene 10, 149–157 (1995).
  CAS PubMed Google Scholar
• Lyman, S. D., Brasel, K., Rousseau, A. M. & Williams, D. E. The flt3 ligand: a hematopoietic stem cell factor whose activities are distinct from steel factor. Stem Cells 12 (Suppl. 1), 99–107; 108–110 (1994).
  PubMed Google Scholar
• Brasel, K. et al. Expression of the flt3 receptor and its ligand on hematopoietic cells. Leukemia 9, 1212–1218 (1995).
  CAS PubMed Google Scholar
• Meierhoff, G. et al. Expression of FLT3 receptor and FLT3-ligand in human leukemia–lymphoma cell lines. Leukemia 9, 1368–1372 (1995).
  CAS PubMed Google Scholar
• Spagnoli, G. C. et al. FLT3 ligand gene expression and protein production in human colorectal cancer cell lines and clinical tumor specimens. Int. J. Cancer 86, 238–243 (2000).
  CAS PubMed Google Scholar
• Gonfloni, S., Weijland, A., Kretzschmar, J. & Superti-Furga, G. Crosstalk between the catalytic and regulatory domains allows bidirectional regulation of Src. Nature Struct. Biol. 7, 281–286 (2000).
  CAS PubMed Google Scholar
• Turner, A. M., Lin, N. L., Issarachai, S., Lyman, S. D. & Broudy, V. C. FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells. Blood 88, 3383–3390 (1996).
  CAS PubMed Google Scholar
• Weiss, A. & Schlessinger, J. Switching signals on or off by receptor dimerization. Cell 94, 277–280 (1998).
  CAS PubMed Google Scholar
• Yee, N. S., Langen, H. & Besmer, P. Mechanism of kit ligand, phorbol ester, and calcium-induced down-regulation of c-kit receptors in mast cells. J. Biol. Chem. 268, 14189–14201 (1993).
  CAS PubMed Google Scholar
• Lyman, S. D. 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 86, 4091–4096 (1995).
  CAS PubMed Google Scholar
• Ashihara, E. et al. FLT-3 ligand mobilizes hematopoietic primitive and committed progenitor cells into blood in mice. Eur. J. Haematol. 60, 86–92 (1998).
  CAS PubMed Google Scholar
• Rogers, S. Y., Bradbury, D., Kozlowski, R. & Russell, N. H. Evidence for internal autocrine regulation of growth in acute myeloblastic leukemia cells. Exp. Hematol. 22, 593–598 (1994).
  CAS PubMed Google Scholar
• Dosil, M., Wang, S. & Lemischka, I. R. Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin-3-dependent hematopoietic cells. Mol. Cell. Biol. 13, 6572–6585 (1993).
  CAS PubMed PubMed Central Google Scholar
• Rottapel, R. et al. Substrate specificities and identification of a putative binding site for PI3K in the carboxy tail of the murine Flt3 receptor tyrosine kinase. Oncogene 9, 1755–1765 (1994). References 38 and 39 were two of the first papers to describe the downstream effectors of wild-type FLT3, using a chimeric receptor.
  CAS PubMed Google Scholar
• Marchetto, S. et al. SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Leukemia 13, 1374–1382 (1999).
  CAS PubMed Google Scholar
• Zhang, S., Mantel, C. & Broxmeyer, H. E. Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells. J. Leukocyte Biol. 65, 372–380 (1999).
  CAS PubMed Google Scholar
• Lavagna-Sevenier, C., Marchetto, S., Birnbaum, D. & Rosnet, O. FLT3 signaling in hematopoietic cells involves CBL, SHC and an unknown P115 as prominent tyrosine-phosphorylated substrates. Leukemia 12, 301–310 (1998).
  CAS PubMed Google Scholar
• Zhang, S. & Broxmeyer, H. E. Flt3 ligand induces tyrosine phosphorylation of gab1 and gab2 and their association with shp-2, grb2, and PI3 kinase. Biochem. Biophys. Res. Commun. 277, 195–199 (2000).
  CAS PubMed Google Scholar
• Srinivasa, S. P. & Doshi, P. D. Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways cooperate in mediating cytokine-induced proliferation of a leukemic cell line. Leukemia 16, 244–253 (2002).
  CAS PubMed Google Scholar
• Zhang, S. & Broxmeyer, H. E. p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells. Biochem. Biophys. Res. Commun. 254, 440–445 (1999).
  CAS PubMed Google Scholar
• Zhang, S. et al. Essential role of signal transducer and activator of transcription (Stat)5a but not Stat5b for Flt3-dependent signaling. J. Exp. Med. 192, 719–728 (2000).
  CAS PubMed PubMed Central Google Scholar
• Lisovsky, M. et al. Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax. Blood 88, 3987–3997 (1996).
  CAS PubMed Google Scholar
• Radich, J. P. et al. N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 76, 801–807 (1990).
  CAS PubMed Google Scholar
• Nakagawa, T. et al. Multiple point mutation of N-ras and K-ras oncogenes in myelodysplastic syndrome and acute myelogenous leukemia. Oncology 49, 114–122 (1992).
  CAS PubMed Google Scholar
• Bustelo, X. R., Ledbetter, J. A. & Barbacid, M. Product of vav proto-oncogene defines a new class of tyrosine protein kinase substrates. Nature 356, 68–71 (1992).
  CAS PubMed Google Scholar
• Ray, R. J., Paige, C. J., Furlonger, C., Lyman, S. D. & Rottapel, R. Flt3 ligand supports the differentiation of early B cell progenitors in the presence of interleukin-11 and interleukin-7. Eur. J. Immunol. 26, 1504–1510 (1996).
  CAS PubMed Google Scholar
• Veiby, O. P., Lyman, S. D. & Jacobsen, S. E. Combined signaling through interleukin-7 receptors and flt3 but not c-kit potently and selectively promotes B-cell commitment and differentiation from uncommitted murine bone marrow progenitor cells. Blood 88, 1256–1265 (1996).
  CAS PubMed Google Scholar
• Rusten, L. S., Lyman, S. D., Veiby, O. P. & Jacobsen, S. E. The FLT3 ligand is a direct and potent stimulator of the growth of primitive and committed human CD34+ bone marrow progenitor cells in vitro. Blood 87, 1317–1325 (1996).
  CAS PubMed Google Scholar
• Shah, A. J., Smogorzewska, E. M., Hannum, C. & Crooks, G. M. Flt3 ligand induces proliferation of quiescent human bone marrow CD34+CD38− cells and maintains progenitor cells in vitro. Blood 87, 3563–3570 (1996).
  CAS PubMed Google Scholar
• Namikawa, R., Muench, M. O., de Vries, J. E. & Roncarolo, M. G. The FLK2/FLT3 ligand synergizes with interleukin-7 in promoting stromal-cell-independent expansion and differentiation of human fetal pro-B cells in vitro. Blood 87, 1881–1890 (1996).
  CAS PubMed Google Scholar
• Moore, T. A. & Zlotnik, A. Differential effects of Flk-2/Flt-3 ligand and stem cell factor on murine thymic progenitor cells. J. Immunol. 158, 4187–4192 (1997).
  CAS PubMed Google Scholar
• Mackarehtschian, K. et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3, 147–161 (1995).
  CAS PubMed Google Scholar
• Saunders, D. et al. Dendritic cell development in culture from thymic precursor cells in the absence of granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 184, 2185–2196 (1996).
  CAS PubMed PubMed Central Google Scholar
• Maraskovsky, E. et al. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J. Exp. Med. 184, 1953–1962 (1996).
  CAS PubMed Google Scholar
• Morse, M. A. et al. Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer. J. Clin. Oncol. 18, 3883–3893 (2000).
  CAS PubMed Google Scholar
• Manfra, D. J. et al. Conditional expression of murine flt3 ligand leads to expansion of multiple dendritic cell subsets in peripheral blood and tissues of transgenic mice. J. Immunol. 170, 2843–2852 (2003).
  CAS PubMed Google Scholar
• Lynch, D. H. et al. Flt3 ligand induces tumor regression and antitumor immune responses in vivo. Nature Med. 3, 625–631 (1997).
  CAS PubMed Google Scholar
• Chen, K. et al. Antitumor activity and immunotherapeutic properties of Flt3-ligand in a murine breast cancer model. Cancer Res. 57, 3511–3516 (1997).
  CAS PubMed Google Scholar
• Chakravarty, P. K. et al. Flt3-ligand administration after radiation therapy prolongs survival in a murine model of metastatic lung cancer. Cancer Res. 59, 6028–6032 (1999).
  CAS PubMed Google Scholar
• Pawlowska, A. B. et al. In vitro tumor-pulsed or in vivo Flt3 ligand-generated dendritic cells provide protection against acute myelogenous leukemia in nontransplanted or syngeneic bone marrow-transplanted mice. Blood 97, 1474–1482 (2001).
  CAS PubMed Google Scholar
• Parajuli, P. et al. Immunization with wild-type p53 gene sequences coadministered with Flt3 ligand induces an antigen-specific type 1 T-cell response. Cancer Res. 61, 8227–8234 (2001).
  CAS PubMed Google Scholar
• Disis, M. L. et al. Flt3 ligand as a vaccine adjuvant in association with HER-2/neu peptide-based vaccines in patients with HER-2/neu-overexpressing cancers. Blood 99, 2845–2850 (2002).
  CAS PubMed Google Scholar
• Fong, L. et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc. Natl Acad. Sci. USA 98, 8809–8814 (2001).
  CAS PubMed PubMed Central Google Scholar
• Dehmel, U. et al. Effects of FLT3 ligand on human leukemia cells. I. Proliferative response of myeloid leukemia cells. Leukemia 10, 261–270 (1996).
  CAS PubMed Google Scholar
• Nakao, M. et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10, 1911–1918 (1996). The first article to describe ITDs of FLT3 in leukaemia, leading the way for future articles that examined the prognostic impact of FLT3 mutations.
  CAS PubMed Google Scholar
• Kiyoi, 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 12, 1333–1337 (1998). One of the first papers to show that FLT3 ITDs cause constitutive activation and ligand-independent growth in mouse transduction models. It led to the use of mouse transduction models for molecular-biology investigations of the mutated receptor and potential FLT3 inhibitors.
  CAS PubMed Google Scholar
• Kiyoi, H. 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 11, 1447–1452 (1997).
  CAS PubMed Google Scholar
• Stirewalt, D. L. et al. FLT3, RAS and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 97, 3589–3595 (2001). The only study to examine specifically the prognostic impact of FLT3 ITDs in older adults with AML, which showed that single-strand conformational analyses were more sensitive than previously published means for detecting FLT3 ITDs.
  CAS PubMed Google Scholar
• Meshinchi, S. et al. Prevalence and prognostic significance of FLT3 internal tandem duplication in pediatric acute myeloid leukemia. Blood 97, 89–94 (2001).
  CAS PubMed Google Scholar
• Schnittger, S. 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 100, 59–66 (2002).
  CAS PubMed Google Scholar
• Thiede, C. 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 99, 4326–4335 (2002). References 74–76 are three of the largest studies to examine FLT3 ITDs in paediatric and adult AML.
  CAS PubMed Google Scholar
• Abu-Duhier, F. M. et al. FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br. J. Haematol. 111, 190–195 (2000).
  CAS PubMed Google Scholar
• Horiike, S. et al. Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia 11, 1442–1446 (1997).
  CAS PubMed Google Scholar
• Xu, F. et al. Tandem duplication of the FLT3 gene is found in acute lymphoblastic leukaemia as well as acute myeloid leukaemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukaemia in children. Br. J. Haematol. 105, 155–162 (1999).
  CAS PubMed Google Scholar
• Kiyoi, H. et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 93, 3074–3080 (1999).
  CAS PubMed Google Scholar
• Kottaridis, P. D. 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 98, 1752–1759 (2001).
  CAS PubMed Google Scholar
• Yokota, S. et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia 11, 1605–1609 (1997).
  CAS PubMed Google Scholar
• Yamamoto, Y. et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 97, 2434–2439 (2001).
  CAS PubMed Google Scholar
• Abu-Duhier, F. M. et al. Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br. J. Haematol. 113, 983–988 (2001). References 83 and 84 describe new missense mutations in exon 17 (now referred to as exon 20) of FLT3 in patients with leukaemia.
  CAS PubMed Google Scholar
• Spiekermann, K. et al. A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. Blood 100, 3423–3425 (2002).
  CAS PubMed Google Scholar
• Meshinchi, S. et al. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Blood 102, 1474–1479 (2003).
  CAS PubMed Google Scholar
• Hayakawa, F. et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 19, 624–631 (2000). One of the first studies to describe the downstream effects of constitutively activated FLT3 ITDs.
  CAS PubMed Google Scholar
• 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 21, 2555–2563 (2002). This paper showed that FLT3 ITDs could constitutively activate wild-type FLT3, providing an insight into the mechanism of action of the mutant receptor.
  CAS PubMed Google Scholar
• Mizuki, M. et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 96, 3907–3914 (2000).
  CAS PubMed Google Scholar
• Gille, H. et al. A repressor sequence in the juxtamembrane domain of Flt-1 (VEGFR-1) constitutively inhibits vascular endothelial growth factor-dependent phosphatidylinositol 3′-kinase activation and endothelial cell migration. EMBO J. 19, 4064–4073 (2000).
  CAS PubMed PubMed Central Google Scholar
• Zheng, R., Friedman, A. D. & Small, D. Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations. Blood 100, 4154–4161 (2002).
  CAS PubMed Google Scholar
• Kelly, L. M. et al. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 99, 310–318 (2002).
  CAS PubMed Google Scholar
• Brown, D. et al. A PMLRARα transgene initiates murine acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 94, 2551–2556 (1997). This study eloquently examines the molecular biology and function of FLT3 ITDs, through blocking their effects in transduction models. The results show that FLT3 ITDs probably affect many different cellular processes, including differentiation, which had not been investigated extensively previously.
  CAS PubMed PubMed Central Google Scholar
• Grisolano, J. L., Wesselschmidt, R. L., Pelicci, P. G. & Ley, T. J. Altered myeloid development and acute leukemia in transgenic mice expressing PML-RARα under control of cathepsin G regulatory sequences. Blood 89, 376–387 (1997).
  CAS PubMed Google Scholar
• Kelly, L. M. et al. PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model. Proc. Natl Acad. Sci. USA 99, 8283–8288 (2002). This paper shows that the combination of an FLT3 ITD and t(15;17) causes a leukaemia-like phenotype in mice, which supports the theory that multiple genomic abnormalities might be necessary in most leukaemia cells.
  CAS PubMed PubMed Central Google Scholar
• Knudson, A. G. Jr, Hethcote, H. W. & Brown, B. W. Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc. Natl Acad. Sci. USA 72, 5116–5120 (1975).
  PubMed PubMed Central Google Scholar
• Mizuki, M. et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood 101, 3164–3173 (2002).
  PubMed Google Scholar
• Beghini, A. et al. C-kit mutations in core binding factor leukemias. Blood 95, 726–727 (2000).
  CAS PubMed Google Scholar
• Sperr, W. R. et al. Systemic mastocytosis associated with acute myeloid leukaemia: report of two cases and detection of the c-kit mutation Asp-816 to Val. Br. J. Haematol. 103, 740–749 (1998).
  CAS PubMed Google Scholar
• Tsujimura, T. et al. Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation. Blood 83, 2619–2626 (1994).
  CAS PubMed Google Scholar
• Morley, G. M., Uden, M., Gullick, W. J. & Dibb, N. J. Cell specific transformation by c-fms activating loop mutations is attributable to constitutive receptor degradation. Oncogene 18, 3076–3084 (1999).
  CAS PubMed Google Scholar
• Moriyama, Y. et al. Role of aspartic acid 814 in the function and expression of c-kit receptor tyrosine kinase. J. Biol. Chem. 271, 3347–3350 (1996).
  CAS PubMed Google Scholar
• Iwai, T. et al. Internal tandem duplication of the FLT3 gene and clinical evaluation in childhood acute myeloid leukemia. The Children's Cancer and Leukemia Study Group, Japan. Leukemia 13, 38–43 (1999).
  CAS PubMed Google Scholar
• Kondo, M. et al. Prognostic value of internal tandem duplication of the FLT3 gene in childhood acute myelogenous leukemia. Med. Pediatr. Oncol. 33, 525–529 (1999).
  CAS PubMed Google Scholar
• Libura, M. et al. FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress. Blood Jun 5 2003 (doi: 10.1182/blood-2003-01-0162). This paper was the first to examine the possible correlations between MLL abnormalities and expression of FLT3 in patient samples.
• Shih, L. Y. 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 100, 2387–2392 (2002).
  CAS PubMed Google Scholar
• Alsabeh, R., Brynes, R. K., Slovak, M. L. & Arber, D. A. Acute myeloid leukemia with t(6;9) (p23;q34): association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype. Am. J. Clin. Pathol. 107, 430–437 (1997).
  CAS PubMed Google Scholar
• Noguera, N. I. et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia 16, 2185–2189 (2002).
  CAS PubMed Google Scholar
• Whitman, S. P. 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. 61, 7233–7239 (2001). One of the first studies to indicate that the ITD:wild-type ratio of FLT3 might have prognostic impact in patients with AML.
  CAS PubMed Google Scholar
• Armstrong, S. A. et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell. 3, 173–183 (2003). This study was the first to show that inhibition of FLT3 over-expression in a cell with MLL abnormalities could block the growth of these cells, and it provided the rationale for examining FLT3 inhibitors in other leukaemia cells that over-express FLT3.
  CAS PubMed Google Scholar
• Druker, B. J. & Lydon, N. B. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J. Clin. Invest. 105, 3–7 (2000).
  CAS PubMed PubMed Central Google Scholar
• Zhao, M. et al. In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia 14, 374–378 (2000).
  CAS PubMed Google Scholar
• Levis, M., Tse, K. F., Smith, B. D., Garrett, E. & Small, D. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood 98, 885–887 (2001). References 112 and 113 were the first to show that activation-mutant FLT3 could be blocked with tyrosine-kinase inhibitors, and that this inhibition caused apoptosis.
  CAS PubMed Google Scholar
• Tse, K. F. et al. Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor. Leukemia 16, 2027–2036 (2002).
  CAS PubMed Google Scholar
• Minami, Y. et al. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 16, 1535–1540 (2002).
  CAS PubMed Google Scholar
• Levis, M. et al. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 99, 3885–3891 (2002).
  CAS PubMed Google Scholar
• Levis, M. et al. FLT3-targeted inhibitors kill FLT3-dependent modeled cells, leukemia-derived cell lines, and primary AML blasts in vitro and in vivo. Blood 89, 721a (2001).
  Google Scholar
• Smith, B. D. et al. Single agent CEP-701, a novel FLT-3 inhibitor, shows initial response in patients with refactory acute myeloid leukemia. Blood 100, 314a (2002).
  Google Scholar
• O'Farrell, A. M. et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101, 3597–3605 (2003).
  CAS PubMed Google Scholar
• Yee, K. W. et al. SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood 100, 2941–2949 (2002).
  CAS PubMed Google Scholar
• Foran, J. et al. An innovative single dose clinical study shows potent inhibition of FLT3 phosphorylation by SU11248 in vivo: a clinical and pharmacodynamic study in AML patients. Blood 100, 2196a (2002).
  Google Scholar
• Giles, F. J. et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood 102, 795–801 (2003). One of the first articles to show inhibition of growth and induction of apoptosis in FLT3 ITD-transduced cells using more-selective tyrosine-kinase inhibitors.
  CAS PubMed Google Scholar
• Foran, J. et al. A phase I study of repeated oral dosing with SU11248 for the treatment of patients with acute myeloid leukemia who have failed, or are not eligible for convential chemotherapy. Blood 100, 2195a (2002).
  Google Scholar
• Kelly, L. M. et al. CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell 1, 421–432 (2002).
  CAS PubMed Google Scholar
• Heinrich, M. C. et al. A “first in man” study of the safety and PK/PD of an oral FLT3 inhibitor (MLN518) in patients with AML or high risk myelodysplasia. Blood 100, 1305a (2002).
  Google Scholar
• Weisberg, E. et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 1, 433–443 (2002).
  CAS PubMed Google Scholar
• Stone, R. M. et al. PKC412, an oral FLT3 inhibitor, has activity in mutant FLT3 acute myeloid leukemia (AML): a phase II clinical trial. Blood 100, 316a (2002).
  Google Scholar