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

Ryan Carr , Denis Vorobyev (1) , Terra Lasho , David Marks , Ezequiel Tolosa , Alexis Vedder , Luciana Almada , Andrey Yurcheko (1) , Ismael Padioleau (1) , Bonnie Alver , Giacomo Coltro , Moritz Binder , Stephanie Safgren , Isaac Horn , Xiaona You , Éric Solary (2) , Maria Balasis , Kurt Berger , James Hiebert , Thomas Witzig , Ajinkya Buradkar , Temeida Graf , Peter Valent , Abhishek Mangaonkar , Keith Robertson , Matthew Howard , Scott Kaufmann , Christopher Pin , Martin Fernandez-Zapico , Klaus Geissler , Nathalie Droin (2) , Eric Padron , Jing Zhang , Sergey Nikolaev (1) , Mrinal Patnaik

1 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie
2 Dynamo - Dynamique moléculaire de la transformation hématopoïétique

Abstract 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.

Domaines: Sciences du Vivant [q-bio]

Ryan Carr, Denis Vorobyev, Terra Lasho, David Marks, Ezequiel Tolosa, et al.. RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis. Nature Communications, 2021, 12 (1), pp.2901. ⟨10.1038/s41467-021-23186-w⟩. ⟨hal-04438581⟩