Novel molecular mechanisms of FLT3 deregulation: from the acute myeloid leukemia experience to therapeutic insights in acute lymphoblastic leukemia.

Fms-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase essential for hematopoiesis, is a well-established oncogenic driver in acute myeloid leukemia (AML). Canonical internal tandem duplications (ITD) and tyrosine kinase domain (TKD) mutations inform prognosis and guide targeted therapy. Recent evidence highlights FLT3 as a critical oncogenic hub in acute lymphoblastic leukemia (ALL), where its alterations extend beyond ITD/TKD mutations to include non-canonical mutations with only partially explored functional implications. Moreover, recently discovered regulatory mechanisms, mostly acting on the FLT3 locus, drive FLT3 overexpression in ALL, including transcriptional regulation by rearranged ZNF384, epigenetic modifications, novel circular-RNA URAD::FLT3 fusions, and 13q12.2 deletions leading to enhancer hijacking and topologically associated domain (TAD)-boundary disruptions. The impact of these alterations on leukemogenesis and the possibility to target them in ALL subtypes is discussed here. Data from the Functional Omics Resource of Acute Lymphoblastic Leukemia (FORALL) across B- and T-ALL cell line subtypes drug screening, and from preclinical and clinical evidence reveals a variable efficacy in FLT3-mutated and FLT3-overexpressing ALL subtypes, supporting a molecularly guided treatment approach. Building on the success of FLT3 inhibitors in mutated AML and in light of the emerging results in patients lacking FLT3-ITD and in FLT3-like AML cases, presenting with a gene expression pattern similar to FLT3-mutated ones despite the absence of mutations, we discuss their potential in ALL and we consider novel therapeutic strategies, including new FLT3 inhibitors, antibody-based approaches, FLT3 CAR-T therapy, and synergistic drug combinations, such as FLT3 and BCL2 inhibition. These new insights reviewed here may redefine FLT3 as a pan-leukemic target, with ALL-specific activation mechanisms offering unique therapeutic windows. The implementation of FLT3 expression profiling and full-coding mutation screening in ALL (and in AML) diagnostics could unlock precision medicine approaches. By bridging the AML experience with ALL innovations, this review outlines a roadmap for FLT3-targeted therapies and combination strategies, underscoring the urgency of biomarker-driven clinical trials to optimize FLT3-directed interventions in acute leukemias.