FLT3 Inhibitors in Acute Myeloid Leukemia

Khaled el-Shami; Richard M. Stone; B. Douglas Smith

Disclosures

Expert Rev Hematol. 2008;1(2):153-160. 

In This Article

FLT3 Receptor: Biology

The fms-like tyrosine kinase (FLT3) is a type III receptor tyrosine kinase in the PDGF family of growth factor receptors.[9] It was originally cloned from CD34+ hematopoietic stem cells more than a decade ago by two independent groups.[10,11] FLT3 contains 993 amino acids and is visualized on electrophoresis gels as two distinct bands corresponding to 130 and 160 kDa (the larger band representing the functionally mature fully glycosylated form). FLT3 has an extracellular ligand-binding region with five immunoglobulin-like domains and a single transmembrane domain (Figure 1). The cytoplasmic portion is comprised of a juxtamembrane domain followed by the catalytic domain, which is interrupted by a kinase insert domain. FLT3 ligand (FL) is a type I transmembrane protein expressed on the surface of stromal and hematopoietic cells in the bone marrow and in virtually all cell types examined.[12,13] FL binding induces FLT3 conformational changes, dimerization and activation by cross-phosphorylation of intracytoplasmic tyrosine residues. This autophosphorylation results in the transduction of growth-promoting and apoptosis-inhibitory signals through pathways linked to key cytoplasmic molecules including RAS-GAP, PLC-β, STAT5 and ERK1/2.[14,15,16,17,18,19,20]

Figure 1.

Fms-like tyrosine kinase 3 receptor monomer.

In contrast to its ligand (FL, which seems to be ubiquitously expressed), FLT3 has a narrow tissue-restricted pattern of expression, being primarily localized to hematopoietic and neural tissues, and this confines its function to these tissue compartments.[21] In the bone marrow, FLT3 is expressed predominantly by CD34+ hematopoietic cells and is considered a key receptor in hematopoietic development. Its activation synergizes with other signaling pathways to promote hematopoietic precursor expansion. Targeted disruption of either FLT3 or its ligand results in nonlethal quantitative deficiency in primitive hematopoietic precursors as well as lymphoid and dendritic cells.[21,22,23,24,25,26,27,28]

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