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

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.

Predictive value of pretransplantation molecular minimal residual disease assessment by WT1 gene expression in FLT3-positive acute myeloid leukemia

“…The presence of the FLT3 mutation is a poor prognostic factor in AML patients with a high risk of relapse and short duration of remission [1,3,4,8]. In addition, some recent studies emphasize the prognostic importance of the FLT3 allelic burden (allelic ratio); in particular, an allelic ratio higher than 0.5-0.8 could be associated with a negative prognostic effect determined by the mutation [2,8,25,26]. It is noteworthy that, even if all of Figure 2.…”

“…The FMS-like tyrosine kinase 3 (FLT3) gene, located on chromosome 13, encodes a tyrosine kinase receptor located on the surface of hematopoietic progenitor cells that is essential for cellular survival and differentiation [1][2][3]. FLT3 mutations can involve the receptor juxtamembrane internal tandem duplication (ITD) domain or the intracellular tyrosine kinase domain (TKD) and can cause, in most cases, an autophosphorylation with the constitutive activation of the receptor, resulting in a higher proliferation and an increased survival of leukemic cells [1,3,4].…”

Development and Characterization of FLT3-Specific Curcumin-Loaded Polymeric Micelles as a Drug Delivery System for Treating FLT3-Overexpressing Leukemic Cells

“…On the other hand, FLT3 causes the activation of phosphatidylinositol-3-kinase (PI3K) which stimulates protein kinase B or AKT protein that regulates many downstream proteins involve in cell survival and anti-apoptosis. 56 Thus, the inhibition of FLT3 protein expression by CM in the cell lines used in this study might inhibit the activity of PI3K and its downstream effectors to promote cell survival and anti-apoptosis. Previous studies also reported that CM directly inhibited PI3K and anti-apoptotic protein (B-cell lymphoma 2 or Bcl-2) expression.…”

A Genome-Wide CRISPR Screen Identifies Genes Critical for Resistance to FLT3 Inhibitor AC220

“…FLT3-ITD mutation leads to constitutive activation of FLT3 kinase, with subsequent constitutive activation of its downstream signaling pathways including Ras/MAPK kinase pathway, STAT5, and PI3K/Akt pathway (9,10). Moreover, it was also reported that crosstalk between FLT3 and Wnt pathways plays a critical role in the pathogenesis of FLT3-ITD + AML (35,36).…”

“…It is associated with worse prognosis and adverse disease outcome (4–7). Mechanistically, FLT3-ITD mutations result in loss of the auto inhibitory function and subsequent constitutive activation of FLT3 kinase as well as its downstream proliferative signaling pathways, including the Ras/MAPK/ERK pathway, STAT5 and PI3K/Akt/mTOR pathway (8–10). Clinically, FLT3-ITD mutations are present in roughly 20% of adult AML cases.…”