Transcriptional control of CBX5 by the RNA binding proteins RBMX and RBMXL1 maintains chromatin state in myeloid leukemia.

Autor: Prieto C; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Nguyen DTT; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Liu Z; Program for Mathematical Genomics, Department of Systems Biology, Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.; CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing 100101, China., Wheat J; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY USA., Perez A; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Gourkanti S; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chou T; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Barin E; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Velleca A; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Rohwetter T; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Chow A; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Taggart J; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Savino AM; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Hoskova K; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Dhodapkar M; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Schurer A; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Barlowe TS; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Vu LP; Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC, Canada; Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada., Leslie C; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Steidl U; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY USA., Rabadan R; Program for Mathematical Genomics, Department of Systems Biology, Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA., Kharas MG; Molecular Pharmacology Program and Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2021 Jul; Vol. 2, pp. 741-757. Date of Electronic Publication: 2021 Jul 05.
DOI: 10.1038/s43018-021-00220-w
Abstrakt: RNA binding proteins (RBPs) are key arbiters of post-transcriptional regulation and are found to be found dysregulated in hematological malignancies. Here, we identify the RBP RBMX and its retrogene RBMXL1 to be required for murine and human myeloid leukemogenesis. RBMX/L1 are overexpressed in acute myeloid leukemia (AML) primary patients compared to healthy individuals, and RBMX/L1 loss delayed leukemia development. RBMX/L1 loss lead to significant changes in chromatin accessibility, as well as chromosomal breaks and gaps. We found that RBMX/L1 directly bind to mRNAs, affect transcription of multiple loci, including CBX5 (HP1α), and control the nascent transcription of the CBX5 locus. Forced CBX5 expression rescued the RBMX/L1 depletion effects on cell growth and apoptosis. Overall, we determine that RBMX/L1 control leukemia cell survival by regulating chromatin state through their downstream target CBX5 . These findings identify a mechanism for RBPs directly promoting transcription and suggest RBMX/L1, as well as CBX5, as potential therapeutic targets in myeloid malignancies.
Databáze: MEDLINE
Externí odkaz: