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

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Proliferative chronic myelomonocytic leukemia (pCMML) is an aggressive subtype with poor prognosis.
• RAS pathway mutations, particularly NRAS^G12D, are key drivers of the pCMML phenotype.
• These mutations can accelerate the progression of CMML to acute myeloid leukemia.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying pCMML.
• To identify potential therapeutic targets for pCMML.
• To evaluate the efficacy of personalized, biomarker-driven treatments.

Main Methods:

• Exome sequencing and progenitor colony assays were performed.
• A Vav-Cre-Nras^G12D mouse model was utilized.
• Multiomics, biochemical, and molecular studies were conducted, including analysis of gene expression and histone modifications.

Main Results:

• RAS pathway mutations define the pCMML phenotype and promote leukemic transformation.
• pCMML exhibits a distinct gene expression profile enriched in mitotic kinases like polo-like kinase 1 (PLK1).
• PLK1 expression is regulated by KMT2A, leading to epigenetic changes (histone H3 lysine 4 monomethylation).

Conclusions:

• RAS mutations are central to pCMML pathogenesis and progression.
• PLK1 is a critical downstream effector in RAS-mutant pCMML.
• Pharmacologic inhibition of PLK1 in patient-derived xenografts suggests a viable personalized therapeutic strategy for pCMML.