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

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...

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Main Authors: Van Den Berk, Paul, Lancini, Cesare, Company, Carlos, Serresi, Michela, Hulsman, Danielle, Pritchard, Colin, Ji-Ying, Song, Schmitt, Matthias Jurgen, Tanger, Ellen, Huijbers, Ivo J, Jacobs, Heinz, Maarten Van Lohuizen, Gargiulo, Gaetano, Citterio, Elisabetta
Format: Paper
Language:English
Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 24.01.2020
Cold Spring Harbor Laboratory
Edition:1.1
Subjects:
Genetics
Genomes
Genotoxicity
Hematopoietic stem cells
Leukemia
Myeloid leukemia
Progenitor cells
Rodents
Stem cell transplantation
Ubiquitin
Ubiquitin-specific proteinase
Ubiquitination
USP15
shRNA screen
Genome Integrity
Deubiquitinase
Hematopoietic Stem Cell (HSC)
Leukemia
Deubiquitinating Enzymes
DNA Damage
ISSN:2692-8205, 2692-8205
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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.
AbstractList 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.
Author Pritchard, Colin
Schmitt, Matthias Jurgen
Gargiulo, Gaetano
Van Den Berk, Paul
Company, Carlos
Huijbers, Ivo J
Ji-Ying, Song
Hulsman, Danielle
Jacobs, Heinz
Tanger, Ellen
Maarten Van Lohuizen
Citterio, Elisabetta
Lancini, Cesare
Serresi, Michela
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Keywords USP15
shRNA screen
Genome Integrity
Deubiquitinase
Hematopoietic Stem Cell (HSC)
Leukemia
Deubiquitinating Enzymes
DNA Damage
Language English
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Snippet Altering ubiquitination by disruption of individual deubiquitinating enzymes (DUBs) has proven to affect hematopoietic stem cell (HSC) maintenance. However,...
SourceID biorxiv
proquest
SourceType Open Access Repository
Aggregation Database
SubjectTerms Genetics
Genomes
Genotoxicity
Hematopoietic stem cells
Leukemia
Myeloid leukemia
Progenitor cells
Rodents
Stem cell transplantation
Ubiquitin
Ubiquitin-specific proteinase
Ubiquitination
Title USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells
URI https://www.proquest.com/docview/2344445585
https://www.biorxiv.org/content/10.1101/2020.01.23.916627
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