Landscape and clinicopathologic features of RAS pathway mutations in chronic myelomonocytic leukemia Open Access

• Mutations in distinct RAS-pathway genes have unique clonal architecture and cooperate with other genomic events to drive outcomes in CMML.

• Refined genomic classifications and development of novel RAS-directed therapies are urgently needed for patients with CMML

RAS pathway mutations (RASMT) induce proliferative features and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASMT remain unexplored. To characterize the landscape, architecture and implications of unique RASMT in CMML we evaluated a cohort of 814 patients with CMML. We identified 461 RASMT among 342 (42%) patients. N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1 and PTPN11 mutations spanned throughout the gene structure and frequently appeared as subclonal events (75%, 64%, 59%, respectively). CBL mutations frequently occurred in co-dominance with SRSF2 and multihit TET2 and were enriched for KIT mutations. PTPN11 mutations more frequently co-occurred with SETBP1 and DNMT3A mutations and where infrequently co-dominant with TET2 or ASXL1. RASMT predicted for shorter overall-survival (HR 1.55, 95% CI 1.15-2.07, p=0.0075) and leukemia-free survival (LFS, HR 1.67, 95% CI 1.26-2.20, p=0.0011), influenced outcomes of myelodysplastic and TET2 mutant CMML and cooperated with IDH2 and RUNX1 mutations to induce shorter LFS. This data sets the bases for refined genomic classifications of CMML and underscores the need to develop RAS-directed therapies for patients with CMML.