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

Authors

Ryan M. Carr, Mayo Clinic
Denis Vorobyev, Institut de Cancerologie Gustave Roussy
Terra Lasho, Mayo Clinic
David L. Marks, Mayo Clinic
Ezequiel J. Tolosa, Mayo Clinic
Alexis Vedder, Moffitt Cancer Center
Luciana L. Almada, Mayo Clinic
Andrey Yurcheko, Institut de Cancerologie Gustave Roussy
Ismael Padioleau, Institut de Cancerologie Gustave Roussy
Bonnie Alver, Mayo Clinic
Giacomo Coltro, Mayo Clinic
Moritz Binder, Mayo Clinic
Stephanie L. Safgren, Mayo Clinic
Isaac Horn, Mayo Clinic
Xiaona You, McArdle Laboratory for Cancer Research
Eric Solary, Institut de Cancerologie Gustave Roussy
Maria E. Balasis, Moffitt Cancer Center
Kurt Berger, Lawson Health Research Institute
James Hiebert, Mayo Clinic
Thomas Witzig, Mayo Clinic
Ajinkya Buradkar, Mayo Clinic
Temeida Graf, Medizinische Universität Wien
Peter Valent, Medizinische Universität Wien
Abhishek A. Mangaonkar, Mayo Clinic
Keith D. Robertson, Mayo Clinic
Matthew T. Howard, Mayo Clinic
Scott H. Kaufmann, Mayo Clinic
Christopher Pin, Lawson Health Research InstituteFollow
Martin E. Fernandez-Zapico, Mayo Clinic

Document Type

Article

Publication Date

12-1-2021

Journal

Nature Communications

Volume

12

Issue

1

URL with Digital Object Identifier

10.1038/s41467-021-23186-w

Abstract

Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D 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.