Roles of FMS-like Tyrosine Kinase 3 and Isocitrate Dehydrogenase Mutations in the Pathogenesis and Treatment of Acute Myeloid Leukemia

Abstract: Clonal proliferation regarding immature myeloid precursors as well as subsequent bone marrow failure is hallmarks of acute myeloid leukemia (AML), which is a clinically and biologically heterogeneous hematologic malignancy. Frontline therapy is still mostly reliant on cytotoxic chemotherapy, which commonly results in relapse and refractory disease, despite notable advancements in molecular profiling. The therapeutic challenges of AML reflect its multifactorial etiology, encompassing germline predispositions, acquired somatic mutations, prior cytotoxic exposure, infections, and environmental risk factors. Emerging genomic data reveal that distinct DNA copy number variations and single nucleotide polymorphism signatures are associated with differential posttransplant survival outcomes. Among recurrent driver mutations, alterations in FMS-like tyrosine kinase 3 (FLT3) as well as isocitrate dehydrogenase (IDH1/2) genes are among the most prevalent, conferring both prognostic significance and actionable therapeutic potential. FLT3 and IDH mutations contribute to leukemogenesis through dysregulated signaling and metabolic reprogramming, respectively, and have become key targets in precision therapy paradigms. This review analyses the current understanding regarding pathogenic and therapeutic roles of FLT3 and IDH mutations in AML, elucidating the sequential evolution and cooperative interactions of these genetic mutations which may be essential for refining risk stratification, optimizing treatment sequencing, and advancing targeted therapeutic strategies to improve patient outcomes.