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The role of FLT3 in haematopoietic malignancies

Key Points

  • 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.

Abstract

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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Figure 1: Expression of FLT3 in normal haematopoiesis.
Figure 2: Structure and activation of wild-type FLT3.
Figure 3: The FLT3 signalling cascade.
Figure 4: Structure and location of FLT3 mutations.

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Acknowledgements

This work was supported by grants from the National Institutes of Health.

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Correspondence to Derek L. Stirewalt.

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DATABASES

Cancer.gov

leukaemia

LocusLink

ABL

BAX

BCR

CBL

CBLB

CSF1

EPO

FLT3

Flt3

FLT3L

Flt3l

GAB2

G-CSF

GM-CSF

Grb2

HER2/NEU

HSP90

IL-3

IL-6

IL-7

IL-11

FMS

KIT

KIT ligand

MLL

p85

PDGFRA

PDGFRB

Plcγ1

PML

RARA

Ship

SHP2

STAT5A

Vav

VEGFR1

VEGFR2

Glossary

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.

PARACRINE

An effect in a cell that is caused by stimulation by hormones secreted from another cell.

AUTOCRINE

An effect in a cell that is caused by stimulation by hormones secreted from the same cell.

LEUKOCYTOSIS

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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