FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) involved in the proliferation, differentiation and apoptosis of haematopoietic cells. It is mainly expressed by early myeloid and lymphoid progenitor cells.
Many cells of the haematopoietic system produce FLT3 ligand (FLT3L), which promotes dimerization and activation of FLT3. The activated receptor then activates the phosphatidylinositol 3-kinase (PI3K) and RAS signal-transduction cascades.
The FLT3 internal tandem duplication (ITD) results from a head-to-tail duplication of 3–400 base pairs in exons 14 or 15, which encode the juxtamembrane domain of FLT3.
Point mutations in FLT3 occur in heavily conserved areas of the intracellular tyrosine-kinase domain (TKD), homologous to point mutations that are seen in other RTKs such as KIT and FMS.
FLT3 mutations are the most frequent genetic lesion seen in acute myeloid leukaemia (AML). The prevalence of FLT3 ITDs is 15–35%, with an additional 5–10% of patients having FLT3 TKD mutations.
Both types of FLT3 mutation cause ligand-independent activation of the receptor and activation of downstream signalling pathways.
The presence of a FLT3 ITD is associated with poor clinical outcome in both paediatric and adult patients with AML.
Several drugs that target FLT3 are in early clinical trials.
Normal haematopoietic cells use complex systems to control proliferation, differentiation and cell death. The control of proliferation is, in part, accomplished through the ligand-induced stimulation of receptor tyrosine kinases, which signal to downstream effectors through the RAS pathway. Recently, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, which encodes a receptor tyrosine kinase, have been found to be the most common genetic lesion in acute myeloid leukaemia (AML), occurring in ∼25% of cases. Exploring the mechanism by which these FLT3 mutations cause uncontrolled proliferation might lead to a better understanding of how cells become cancerous and provide insights for the development of new drugs.
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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.
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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).
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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.
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.
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).
Zhao, M. et al. In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia 14, 374–378 (2000).
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.
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).
Minami, Y. et al. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 16, 1535–1540 (2002).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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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).
This work was supported by grants from the National Institutes of Health.
- FANCONI ANAEMIA
An autosomal-dominant disorder that is characterized by skeletal growth abnormalities and a high incidence of malignancies, especially of the bone marrow.
- APLASTIC ANAEMIA
An acquired injury to the bone marrow that causes a decrease in normal haematopoesis. This leads to potentially fatal complications from low numbers of red and white blood cells and platelets.
An effect in a cell that is caused by stimulation by hormones secreted from another cell.
An effect in a cell that is caused by stimulation by hormones secreted from the same cell.
An abnormal increase in the number of white blood cells.
- LOSS OF HETEROZYGOSITY
(LOH). A loss of one of the alleles at a given locus as a result of a genomic change, such as mitotic deletion, gene conversion or chromosome missegregration.
- HOMOLOGOUS RECOMBINATION
The process by which segments of DNA are exchanged between two DNA duplexes that share high sequence similarity.
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Stirewalt, D., Radich, J. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 3, 650–665 (2003). https://doi.org/10.1038/nrc1169
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