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USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

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Title:USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells
Creators Name:van den Berk, P. and Lancini, C. and Company, C. and Serresi, M. and Hulsman, D. and Pritchard, C. and Song, J.Y. and Schmitt, M.J. and Tanger, E. and Huijbers, I.J. and Jacobs, H. and van Lohuizen, M. and Gargiulo, G. and Citterio, E.
Abstract:Altering ubiquitination by disruption of individual deubiquitinating enzymes (DUBs) has proven to affect hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. To accomplish this goal, we systematically inactivated DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNAs (shRNAs) screens. We found that multiple DUBs may be individually required for hematopoiesis and that the ubiquitin-specific protease 15 (USP15) is particularly important for the maintenance of murine hematopoietic stem and progenitor cells in vitro and in vivo. Consistently, Usp15 knockout mice exhibited a reduced HSC pool. The defect was intrinsic to HSCs, as demonstrated by competitive repopulation assays. Importantly, USP15 is highly expressed in normal human hematopoietic cells and leukemias, and USP15 depletion in murine early progenitors and myeloid leukemia cells impaired in vitro expansion and increased genotoxic stress. Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSC and in leukemia cells.
Keywords:Hematopoietic Stem Cell (HSC), USP15, Deubiquitinating Enzymes, Deubiquitinase, In Vivo shRNA Screen, Leukemia, DNA Damage, Genome Integrity
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.01.23.916627
Date:24 January 2020
Official Publication:https://doi.org/10.1101/2020.01.23.916627

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