@article{141a3aeae71843c28049da02617bfc3f,
title = "RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis",
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.",
author = "Carr, {Ryan M.} and Denis Vorobyev and Terra Lasho and Marks, {David L.} and Tolosa, {Ezequiel J.} and Alexis Vedder and Almada, {Luciana L.} and Andrey Yurcheko and Ismael Padioleau and Bonnie Alver and Giacomo Coltro and Moritz Binder and Safgren, {Stephanie L.} and Isaac Horn and Xiaona You and Eric Solary and Balasis, {Maria E.} and Kurt Berger and James Hiebert and Thomas Witzig and Ajinkya Buradkar and Temeida Graf and Peter Valent and Mangaonkar, {Abhishek A.} and Robertson, {Keith D.} and Howard, {Matthew T.} and Kaufmann, {Scott H.} and Christopher Pin and Fernandez-Zapico, {Martin E.} and Klaus Geissler and Nathalie Droin and Eric Padron and Jing Zhang and Sergey Nikolaev and Patnaik, {Mrinal M.}",
note = "Funding Information: Current publication is supported in part by grants from the “Gerstner Family Career Development Award”, The “Center for Individualized Medicine-Mayo Clinic”, and “The Henry J. Predolin Foundation for Research in Leukemia, Mayo Clinic, Rochester, MN, USA”. This publication was also supported by CTSA Grant Number KL2 TR000136 from the National Center for Advancing Translational Science (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. R.M.C. was supported by the 2020 Eagles 5th District Cancer Telethon Cancer Research Fund Fellowship Award. M.E.F.Z. was supported by CA136526. S.I.N. was supported by Foundation ARC 2017, Foundation Gustave Roussy and Swiss Cancer League (grant KFC-3985-08-2016) grants. ES group is labeled “Equipe labellis{\'e}e de la Ligue Nationale Contre le Cancer and supported by the French National Cancer Institute. P.V. was supported by the Austrian National Science Fund (FWF) grants F4704-B20 and P30625-B28. A.A.M was supported by the Conquer Cancer Foundation of American Society of Clinical Oncology (ASCO) Young Investigator Award (YIA) and Grant. We would like to thank the University of Wisconsin Carbone Comprehensive Cancer Center (UWCCC) for use of its Shared Services (Flow Cytometry Laboratory, Genome Editing and Animal Models Shared Resource, and Experimental Pathology Laboratory) to complete this research. This work was supported by R01CA152108 and a Scholar Award from the Leukemia & Lymphoma Society to J.Z. This work was also supported in part by NIH/NCI P30 CA014520-UW-Comprehensive Cancer Center Support. The diagram in Supplementary Fig. 7A was created using BioRender.com. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-23186-w",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}