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Review
. 2012 Apr 17;6(1):e8.
doi: 10.4081/oncol.2012.e8. eCollection 2012 Mar 5.

An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment

Tiziana Grafone  1 , Michela Palmisano  2 , Chiara Nicci  1 , Sergio Storti  1
Affiliations
Free PMC article
Review

An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment

Tiziana Grafone et al. Oncol Rev. .
Free PMC article

Abstract

Hematopoiesis, the process by which the hematopoietic stem cells and progenitors differentiate into blood cells of various lineages, involves complex interactions of transcription factors that modulate the expression of downstream genes and mediate proliferation and differentiation signals. Despite the many controls that regulate hematopoiesis, mutations in the regulatory genes capable of promoting leukemogenesis may occur. The FLT3 gene encodes a tyrosine kinase receptor that plays a key role in controlling survival, proliferation and differentiation of hematopoietic cells. Mutations in this gene are critical in causing a deregulation of the delicate balance between cell proliferation and differentiation. In this review, we provide an update on the structure, synthesis and activation of the FLT3 receptor and the subsequent activation of multiple downstream signaling pathways. We also review activating FLT3 mutations that are frequently identified in acute myeloid leukemia, cause activation of more complex downstream signaling pathways and promote leukemogenesis. Finally, FLT3 has emerged as an important target for molecular therapy. We, therefore, report on some recent therapies directed against it.

Keywords: FLT3 receptor; acute myeloid leukemia; inhibitors.; internal tandem duplication; signal transduction networks.

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Conflict of interest statement

Conflict of interests: the authors declare no potential conflict of interests.

Figures

Figure 1
Figure 1
Schematic presentation of FLT3 receptor monomer. ECD, extracellular domain; PM, plasma membrane; CP, cytoplasm; TM, transmembrane domain; JM, juxtamembrane domain; TK1, first tyrosine kinase domain, N-lobe; KI, kinase insert; TK2, second tyrosine kinase domain, C-lobe; AL, activation loop.
Figure 2
Figure 2
Activation of FLT3. A) Inactive conformation; B) Active conformation. Juxtamembrane domain (yellow), activation-loop (green), catalitic loop (red). P, phosphorylation site; N, N-lobe, TK1 domain; C, C-lobe, TK2 domain; ITD, internal tandem duplications; JM-PMs, point mutation in the juxtamembrane domain; TKD, point mutation in the tyrosine kinase domain; FL, FLT3 ligand.
Figure 3
Figure 3
Signaling pathways activated by FLT3-WT.
Figure 4
Figure 4
Signaling pathways activated by FLT3-ITD.
See this image and copyright information in PMC

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