RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis

Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRAS(G12D), define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-Nras(G12D) mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML. Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target.

Automated summary

The research focuses on the relationship between proliferative chronic myelomonocytic leukemia (pCMML) and RAS pathway mutations, revealing that RAS mutations lead to a unique gene expression profile enriched in mitotic kinases such as PLK1. The study suggests that inhibiting RAS-driven PLK1 expression could be a viable therapeutic target for pCMML.