ISSN 2997-1036
International Journal of Hematology | Vol. 9, No. 7, July 2018 | pp. 49–56
DOI: 10.46882/2018/IJH/000103
Review Article
Title: Structural architecture and chemical inhibition mechanisms of the FLT3 receptor tyrosine kinase pathways in acute myeloid leukemia cells
Names of Authors: M. A. Bello¹, O. R. Eze²
Authors’ Affiliations: ¹Department of Haematology, Aminu Kano Teaching Hospital, Kano, Nigeria; ²Department of Pathology, University of Benin, Benin City, Nigeria
Abstract: Activating mutations in the Fms-like tyrosine kinase 3 (FLT3) receptor occur frequently in acute myeloid leukemia, translating to a high relapse rate and short survival duration. This review synthesizes current knowledge on the molecular structural architecture of FLT3 mutations, contrasting internal tandem duplications (FLT3-ITD) within the juxtamembrane domain with point mutations in the tyrosine kinase domain (FLT3-TKD). These structural alterations disrupt auto-inhibitory loops, leading to continuous ligand-independent autophosphorylation and the activation of downstream STAT5, MAPK, and PI3K/Akt signaling networks. Traditional intensive chemotherapy regimens fail to achieve durable remission in patients with high FLT3-ITD mutant allele fractions. Evolving clinical models highlight the therapeutic integration of small-molecule FLT3 inhibitors. First-generation multi-kinase inhibitors like midostaurin and selective second-generation agents like gilteritinib act by blocking ATP-binding pockets within the mutated kinase domains. However, secondary drug resistance often emerges via novel point mutations or microenvironmental cytokine overrides. This review provides a clinical decision-making algorithm incorporating early molecular testing, mutant allele ratio calculation, and maintenance inhibitor pathways to maximize survival outcomes in FLT3-mutated acute myeloid leukemia.
Keywords: Acute myeloid leukemia, FLT3-ITD mutation, juxtamembrane domain, gilteritinib, tyrosine kinase inhibitor
Manuscript Timeline: Received: April 15, 2018; Revised: May 22, 2018; Accepted: June 12, 2018; Published: July 18, 2018