Abstract
SummaryAltering ubiquitination by disruption of deubiquitinating enzymes (DUBs) affects hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. Here, we systematically inactivate DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNA (shRNA) screens. We find that multiple DUBs may be individually required for hematopoiesis and identify ubiquitin-specific protease 15 (USP15) as essential for HSC maintenance in vitro and in transplantations and Usp15 knockout (KO) mice in vivo. USP15 is highly expressed in human hematopoietic tissues and leukemias. USP15 depletion in murine progenitors and leukemia cells impairs in vitro expansion and increases genotoxic stress. In leukemia cells, USP15 interacts with and stabilizes FUS (fused in sarcoma), a known DNA repair factor, directly linking USP15 to the DNA damage response (DDR). Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSCs and leukemia cells.
Highlights
Hematopoietic stem cells (HSCs) have the unique properties of self-renewal and multilineage potential, giving rise to daughter stem cells and committed progenitors, thereby achieving lifelong hematopoiesis
We systematically inactivate deubiquitinating enzymes (DUBs) in mouse hematopoietic progenitors using in vivo small hairpin RNA screens
We find that multiple DUBs may be individually required for hematopoiesis and identify ubiquitin-specific protease 15 (USP15) as essential for HSC maintenance in vitro and in transplantations and Usp15 knockout (KO) mice in vivo
Summary
Hematopoietic stem cells (HSCs) have the unique properties of self-renewal and multilineage potential, giving rise to daughter stem cells and committed progenitors, thereby achieving lifelong hematopoiesis. This is accomplished by maintenance of a homeostatic balance among HSC quiescence, self-renewal, and differentiation (de Haan and Lazare, 2018; Laurenti and Gottgens, 2018; Morrison and Spradling, 2008). Perturbation of this balance and replication stress can cause stem cell failure or transform normal HSCs and progenitors into disease-initiating leukemic stem cells (LSCs) (Flach et al, 2014). Deregulation of DUBs is implicated in human pathologies, such as cancer and neurodegenerative, hematological, and infectious diseases (Heideker and Wertz, 2015)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
