RT Journal Article
SR Electronic
T1 USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.23.916627
DO 10.1101/2020.01.23.916627
A1 Paul van den Berk
A1 Cesare Lancini
A1 Carlos Company
A1 Michela Serresi
A1 Danielle Hulsman
A1 Colin Pritchard
A1 Ji-Ying Song
A1 Matthias Jürgen Schmitt
A1 Ellen Tanger
A1 Ivo J. Huijbers
A1 Heinz Jacobs
A1 Maarten van Lohuizen
A1 Gaetano Gargiulo
A1 Elisabetta Citterio
YR 2020
UL http://biorxiv.org/content/early/2020/01/24/2020.01.23.916627.abstract
AB 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.