@article{1b075c027e8641bfb7fe964349b0bccc,
title = "Transcriptional control of CBX5 by the RNA-binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia",
abstract = "RNA-binding proteins (RBPs) are key arbiters of post-transcriptional regulation and are found to be dysregulated in hematological malignancies. Here we identify the RBP RNA-binding motif protein, X-linked (RBMX; also known as hnRNPG), and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX and RBMXL1 were overexpressed in individuals with acute myeloid leukemia (AML) compared to healthy individuals, and RBMX/RBMXL1 loss delayed leukemia development. RBMX/RBMXL1 loss lead to global changes in chromatin accessibility as well as chromosomal breaks and gaps. We found that RBMX and RBMXL1 directly bind to mRNAs, affect transcription of multiple loci, including CBX5 (also known as heterochromatin protein 1 alpha (HP1-α)), and control the nascent transcription of the CBX5 locus. Forced CBX5 expression rescued the RBMX/RBMXL1 depletion effects on cell growth and apoptosis. Overall, we determined that RBMX and RBMXL1 control leukemia cell survival by regulating chromatin state through the downstream target CBX5. These findings identify a mechanism for RBPs directly promoting transcription and suggest RBMX and RBMXL1, as well as CBX5, as potential therapeutic targets in myeloid malignancies.",
author = "Camila Prieto and Nguyen, {Diu T.T.} and Zhaoqi Liu and Justin Wheat and Alexendar Perez and Saroj Gourkanti and Timothy Chou and Ersilia Barin and Anthony Velleca and Thomas Rohwetter and Arthur Chow and James Taggart and Savino, {Angela M.} and Katerina Hoskova and Meera Dhodapkar and Alexandra Schurer and Barlowe, {Trevor S.} and Vu, {Ly P.} and Christina Leslie and Ulrich Steidl and Raul Rabadan and Kharas, {Michael G.}",
note = "Funding Information: We thank members of the Kharas laboratory for their discussions, helpful advice and suggestions. We also thank the MSKCC Integrated Genomics Operation (IGO), Epigenetics Technology Innovation Lab and Molecular Cytogenetics Core for their technical support. We thank K. Birmingham for her technical support. M.G.K. is a Scholar of the Leukemia and Lymphoma Society and is supported by the US NIH National Institute of Diabetes Digestive and Kidney Diseases Career Development Award NIDDK NIH R01-DK101989-01A1; NCI 1R01CA193842-01, 1R01CA193842-06A1, 5R01CA186702-07, 1R01DK1010989-06A1, R01HL135564 and R01CA225231-01; NYSTEM 0266-A121-4609, the Kimmel Scholar Award; the V-Scholar Award; the Geoffrey Beene Award; the Starr Cancer Consortium; the Alex{\textquoteright}s Lemonade Stand A Award; the LLS Translation Research Program; the Susan and Peter Solomon Fund and the Tri-Institutional Stem Cell Initiative 2016-014. C.P. is supported by an NIDDK Research Supplement to Promote Diversity in Health-Related Research (3R01DK101989-03S1). D.T.T.N. is supported by a Scholar Award from the American Society of Hematology. A.M.S. is supported by the Lauri Strauss Leukemia Foundation and AIL (Associazione Italiana contro Leucemie, Linfomi e Mielomi) through SIES (Societa{\textquoteright} Italiana Ematologia Sperimentale), and L.P.V. is supported by K99 CA229993 and the LLS Career Development Award. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = jul,
doi = "10.1038/s43018-021-00220-w",
language = "English (US)",
volume = "2",
pages = "741--757",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "7",
}
