AML-666: Mutational Landscape of the RTK-RAS Signaling Pathway in Acute Myeloid Leukemia: Insights From Whole-Exome Sequencing

<h3>Background</h3> Acute myeloid leukemia (AML) is driven by concurrent mutations that play roles in leukemogenesis and relapse mechanisms. The RTK-RAS signaling pathway, crucial for cell proliferation, differentiation, and apoptosis, often undergoes genetic alterations, yet the prevalence of these mutations in AML remains unclear. This study delineates the mutation profile of genes associated with the RTK-RAS signaling pathways using whole-exome sequencing (WES). <h3>Methods</h3> Bone marrow and peripheral blood samples were collected from 10 AML patients after obtaining informed consent. Genomic DNA was extracted using the salting-out method, and libraries were prepared according to the manufacturer's instructions. Exonic regions were captured using the TruSeq Exome kit, covering ≥80% of the whole exome, and sequencing was performed on the Illumina platform with a mean depth coverage of 300×. An in-house-developed pipeline was used to analyze the mutational frequency of RTK-RAS signaling pathways. <h3>Results</h3> The RTK-RAS signaling pathway exhibited the highest mutation frequency among the 10 canonical pathways, with alterations identified in all 10 patients. A total of 77 mutated genes were identified, including 4 driver genes and 41 passenger genes. <i>ALK</i>, <i>FGFR1</i>, <i>FLT3</i>, <i>PDGFRB</i>, <i>RIT1</i>, and <i>BRAF</i> were frequently mutated. Specifically, <i>ALK</i> had the highest somatic mutation rate at 80%, followed by <i>FGFR1</i> and <i>FLT3</i> (60% each), whereas <i>PDGFRB</i>, <i>RIT1</i>, and <i>BRAF</i> were altered in 40% of cases. <i>ALK</i> mutations comprised missense and frameshift deletions, whereas <i>FGFR1</i> and <i>FLT3</i> mutations included in-frame deletions and missense mutations. <h3>Conclusion</h3> This study highlights <i>ALK</i> and <i>FGFR1</i> as predominantly mutated genes within the RTK-RAS signaling pathway in AML cases. The high incidence of these mutations suggests potential therapeutic targets for high-risk AML. These findings offer promise for improved risk assessment, screening, diagnosis, and prognosis, enhancing the understanding of AML's genetic landscape.