The role of FLT3 in hematopoiesis and leukemia

Harvard University, Cambridge, Massachusetts, United States
Blood (Impact Factor: 10.45). 10/2002; 100(5):1532-42. DOI: 10.1182/blood-2002-02-0492
Source: PubMed


FLT3 is a receptor tyrosine kinase expressed by immature hematopoietic cells and is important for the normal development of stem cells and the immune system. The ligand for FLT3 is expressed by marrow stromal cells and other cells and synergizes with other growth factors to stimulate proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells. Mutations of FLT3 have been detected in about 30% of patients with acute myelogenous leukemia and a small number of patients with acute lymphocytic leukemia or myelodysplastic syndrome. Patients with FLT3 mutations tend to have a poor prognosis. The mutations most often involve small tandem duplications of amino acids within the juxtamembrane domain of the receptor and result in constitutive tyrosine kinase activity. Expression of a mutant FLT3 receptor in murine marrow cells results in a lethal myeloproliferative syndrome and preliminary studies suggest that mutant FLT3 cooperates with other leukemia oncogenes to confer a more aggressive phenotype. Taken together, these results suggest that FLT3 is an attractive therapeutic target for kinase inhibitors or other approaches for patients with mutations of this gene.

Download full-text


Available from: James D Griffin, Jan 21, 2014
1 Follower
66 Reads
  • Source
    • "Another report suggests that over-expression of HOXB6 in NB4 cells or in HL60 cells caused inhibition of the granulocytic and monocytic maturation, respectively [12]. The type III receptor tyrosine kinase FLT3 is expressed in almost all AML, and about 35% of AML patients carry an oncogenic FLT3 mutation [14]. Among the several mutations that have been found, the internal tandem duplication (ITD) of the sequence that encodes the juxtamembrane domain is the most common mutation in FLT3. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous aggressive disease and the most common form of adult leukemia. Mutations in the type III receptor tyrosine kinase FLT3 are found in more than 30% of AML patients. Drugs against FLT3 have been developed for the treatment of AML, but they lack specificity, show poor response and lead to the development of a resistant phenotype upon treatment. Therefore, a deeper understanding of FLT3 signaling will facilitate identification of additional pharmacological targets in FLT3-driven AML. In this report, we identify HOXB2 and HOXB3 as novel regulators of oncogenic FLT3-ITD-driven AML. We show that HOXB2 and HOXB3 expression is upregulated in a group of AML patients carrying FLT3-ITD. Overexpression of HOXB2 or HOXB3 in mouse pro-B cells resulted in decreased FLT3-ITD-dependent cell proliferation as well as colony formation and increased apoptosis. Expression of HOXB2 or HOXB3 resulted in a significant decrease in FLT3-ITD-induced AKT, ERK, p38 and STAT5 phosphorylation. Our data suggest that HOXB2 and HOXB3 act as tumor suppressors in FLT3-ITD driven AML.
    Biochemical and Biophysical Research Communications 10/2015; DOI:10.1016/j.bbrc.2015.10.071 · 2.30 Impact Factor
  • Source
    • "Genetic evaluation plays an integral role in the classification of AML [1] [2] [3]. Approximately 50% of patients with de novo AML have cytogenetics abnormalities. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background. We hereby describe what we believe to be the first reported case of t (14; 15) (q32; q13) associated with acute myeloid leukemia (AML). Methods. PubMed, Embase, and OVID search engines were used to review the related literature and similar published cases. Case. A47-year-old female presented in December 2011 with AML (acute myelomonocytic leukemia) with normal cytogenetics; molecular testing revealed FLT-3 internal tandem duplication (ITD) mutation, while no mutations involving FLT3 D385/I836, NPM1 exon 12, or KIT exons 8 and 17 were detected. She was induced with 7 + 3 (cytarabine + idarubicin) and achieved complete remission after a second induction with high-dose cytarabine (HiDAC) followed by uneventful consolidation. She presented 19 months after diagnosis with relapsed disease. Of note, at relapse cytogenetic analysis revealed t (14; 15) (q32; q13), while FLT-3 analysis showed a codon D835 mutation (no ITD mutation was detected). She proved refractory to the initial clofarabine-based regimen, so FLAG-idarubicin then was used. She continued to have persistent disease, and she was discharged on best supportive care. Conclusion. Based on this single case of AML with t (14; 15) (q32; q13), this newly reported translocation may be associated with refractory disease.
    11/2014; 2014:921240. DOI:10.1155/2014/921240
  • Source
    • "Gilliland and Griffin proposed the two-hit model of leukaemogenesis (Gilliland and Griffin, 2002). In this model, two lesions, each belonging to a different class, collaborate to cause AML when neither is sufficient to do so in isolation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute myeloid leukaemia (AML) is an uncontrolled clonal proliferation of abnormal myeloid progenitor cells in the bone marrow and blood. Advances in cancer genomics have revealed the spectrum of somatic mutations that give rise to human AML and drawn our attention to its molecular evolution and clonal architecture. It is now evident that most AML genomes harbour small numbers of mutations, which are acquired in a stepwise manner. This characteristic, combined with our ability to identify mutations in individual leukaemic cells and our detailed understanding of normal human and murine haematopoiesis, makes AML an excellent model for understanding the principles of cancer evolution. Furthermore, a better understanding of how AML evolves can help us devise strategies to improve the therapy and prognosis of AML patients. Here, we draw from recent advances in genomics, clinical studies and experimental models to describe the current knowledge of the clonal evolution of AML and its implications for the biology and treatment of leukaemias and other cancers.
    Disease Models and Mechanisms 08/2014; 7(8):941-951. DOI:10.1242/dmm.015974 · 4.97 Impact Factor
Show more