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

Ryan M. Carr, Denis Vorobyev, Terra Lasho, David L. Marks, Ezequiel J. Tolosa, Alexis Vedder, Luciana L. Almada, Andrey Yurcheko, Ismael Padioleau, Bonnie Alver, Giacomo Coltro, Moritz Binder, Stephanie L. Safgren, Isaac Horn, Xiaona You, Eric Solary, Maria E. Balasis, Kurt Berger, James Hiebert, Thomas Witzig, Ajinkya Buradkar, Temeida Graf, Peter Valent, Abhishek A. Mangaonkar, Keith D. Robertson, Matthew T. Howard, Scott H. Kaufmann, Christopher Pin, Martin E. Fernandez-Zapico, Klaus Geissler, Nathalie Droin, Eric Padron, Jing Zhang, Sergey Nikolaev () and Mrinal M. Patnaik ()
Additional contact information
Ryan M. Carr: Department of Internal Medicine
Denis Vorobyev: INSERM U981, Gustave Roussy Cancer Center
Terra Lasho: Department of Internal Medicine
David L. Marks: Division of Oncology Research
Ezequiel J. Tolosa: Division of Oncology Research
Alexis Vedder: Moffitt Cancer Center
Luciana L. Almada: Division of Oncology Research
Andrey Yurcheko: INSERM U981, Gustave Roussy Cancer Center
Ismael Padioleau: INSERM U981, Gustave Roussy Cancer Center
Bonnie Alver: Molecular Pharmacology and Experimental Therapeutics
Giacomo Coltro: Department of Internal Medicine
Moritz Binder: Department of Internal Medicine
Stephanie L. Safgren: Division of Oncology Research
Isaac Horn: Division of Oncology Research
Xiaona You: University of Wisconsin-Madison
Eric Solary: Gustave Roussy Cancer Center
Maria E. Balasis: Moffitt Cancer Center
Kurt Berger: Lawson Health Research Institute University of Western Ontario
James Hiebert: Department of Internal Medicine
Thomas Witzig: Department of Internal Medicine
Ajinkya Buradkar: Department of Internal Medicine
Temeida Graf: Medical University of Vienna
Peter Valent: Medical University of Vienna
Abhishek A. Mangaonkar: Department of Internal Medicine
Keith D. Robertson: Molecular Pharmacology and Experimental Therapeutics
Matthew T. Howard: Department of Laboratory Medicine and Pathology
Scott H. Kaufmann: Department of Internal Medicine
Christopher Pin: Lawson Health Research Institute University of Western Ontario
Martin E. Fernandez-Zapico: Division of Oncology Research
Klaus Geissler: Sigmund Freud University Vienna
Nathalie Droin: Gustave Roussy Cancer Center
Eric Padron: Moffitt Cancer Center
Jing Zhang: University of Wisconsin-Madison
Sergey Nikolaev: INSERM U981, Gustave Roussy Cancer Center
Mrinal M. Patnaik: Department of Internal Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23186-w

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