Abstract B010: Mutational landscape of RTK–RAS signaling pathway in acute myeloid leukemia: Insights from whole exome sequencing

Abstract Background: Acute myeloid leukemia (AML) is driven by concurrent genetic alterations that promote leukemogenesis and therapeutic resistance. The receptor tyrosine kinase (RTK)–RAS signaling pathway, a critical regulator of cell proliferation, differentiation, and apoptosis, is frequently altered in myeloid malignancies, yet its comprehensive mutation profile in AML remains incompletely defined. Methods: Bone marrow and peripheral blood samples were collected from 10 newly diagnosed AML patients following informed consent. Genomic DNA was extracted using the salting-out method. Exome libraries were prepared with the TruSeq Exome kit, targeting ≥80% of coding regions, and sequenced on the Illumina platform at a mean depth of 300×. Variant calling and annotation were performed using an in-house bioinformatics pipeline with specific focus on RTK–RAS pathway genes. Results: Among the ten canonical cancer pathways interrogated, the RTK–RAS signaling pathway exhibited the highest mutation frequency, with alterations detected in all patients. A total of 77 mutated genes were identified, including four driver genes and 41 passenger genes. Frequently mutated members included ALK (80%), FGFR1 (60%), FLT3 (60%), PDGFRB (40%), RIT1 (40%), and BRAF (40%). Mutation types comprised missense substitutions, in-frame deletions, and frameshift deletions, with ALK harboring recurrent disruptive variants. The enrichment of ALK and FGFR1 mutations underscores their potential as key contributors to leukemogenesis in this cohort. Conclusions: This first whole exome sequencing study of Indian AML patients highlights a high burden of mutations in RTK–RAS signaling genes, with ALK and FGFR1 emerging as recurrently altered candidates. These findings underscore the translational potential of targeting RTK–RAS pathway components for risk stratification and therapeutic intervention in high-risk AML. Citation Format: HARSH GOEL, PRANAY TANWAR. Mutational landscape of RTK–RAS signaling pathway in acute myeloid leukemia: Insights from whole exome sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B010.