USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells

Abstract

SummarySelf-renewal, replication, and differentiation of hematopoietic stem cells (HSCs) are regulated by cytokines produced by niche cells in fetal liver and bone marrow. HSCs must overcome stresses induced by cytokine deprivation during normal development. In this study, we found that ubiquitin-specific peptidase 10 (USP10) is a crucial deubiquitinase for mouse hematopoiesis. All USP10 knockout (KO) mice died within 1 year because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of long-term HSCs (LT-HSCs) in bone marrow and fetal liver. Such USP10-KO fetal liver exhibited enhanced apoptosis of hematopoietic stem/progenitor cells (HSPCs) including LT-HSCs but not of lineage-committed progenitor cells. Transplantation of USP10-competent bone marrow cells into USP10-KO mice reconstituted multilineage hematopoiesis. These results suggest that USP10 is an essential deubiquitinase in hematopoiesis and functions by inhibiting apoptosis of HSPCs including LT-HSCs.

A case of pediatric acute myeloid leukemia with t(11;16)(q23;q24) leading to a novel KMT2A‐USP10 fusion gene

“…USP10 is shown to inhibit apoptosis in hematopoietic stem cells by reducing the reactive oxygen species (ROS) level and by a ROS-independent mechanisms common to those described for solid tumors. 25 In conclusion, in the present work, we have discovered a new inframe gene fusion, KMT2A/USP10, which identifies a novel and mechanistically interesting translocation partner gene of KMT2A. This novel fusion has been identified in an adolescent case of relapsed AML-M5a with t(11;16)(q23;q24).…”

“…USP10‐deficient mice develop lethal bone marrow failure with pancytopenia which is due to increased apoptosis in long‐term hematopoietic stem cells. USP10 is shown to inhibit apoptosis in hematopoietic stem cells by reducing the reactive oxygen species (ROS) level and by a ROS‐independent mechanisms common to those described for solid tumors …”

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

“…This is in line with a proper DDR being crucial to HSC function (Bakker and Passegue, 2013;Biechonski et al, 2017). Notably, numerous DUBs control ubiquitin-dependent DDR signaling (Citterio, 2015;Jackson and Durocher, 2013;Nishi et al, 2014;Schwertman et al, 2016) and recent studies provided evidence that DUBs deregulation contributes to altered HSC homeostasis and human blood diseases, including myelodysplastic syndrome (MDS) (Adorno et al, 2013;Dey et al, 2012;Gu et al, 2016;Higuchi et al, 2016;Nakagawa et al, 2015), with some of the DUBs primarily impacting on DDR (Citterio, 2015;Lancini et al, 2014;Parmar et al, 2010).…”

“…The success of our shRNA screening approach is underscored by the successful shRNA library representation in Lin-cells, engraftment of transduced cells, detection of a large library representation in vivo in Lin-and in splenic B cells (≥90%) and retrieval of positive shRNAs controls in vivo. Also, shRNAs targeting DUBs previously involved in HSC biology were scored in the screens, in particular USP1 (Parmar et al, 2010), USP3 (Lancini et al, 2014), USP16 (Adorno et al, 2013;Gu et al, 2016) and BAP1 (Dey et al, 2012;Higuchi et al, 2016;Nakagawa et al, 2015;Nijnik et al, 2012;Wang et al, 2013) (Table S3). Together with the extensive genetic validation, these examples raise confidence in the identification of USP15 as critical regulator of HSCs in vivo and validate the use of in vivo genetic screens for systematically characterizing the role of DUBs in tissue homeostasis.…”

“…While recent gene-centric approaches connected DUBs to HSC maintenance (Adorno et al, 2013;Dey et al, 2012;Gu et al, 2016;Higuchi et al, 2016;Lancini et al, 2014;Nakagawa et al, 2015;Nijnik et al, 2012;Parmar et al, 2010;Wang et al, 2013), a comprehensive understanding of DUBs biological functions in hematopoiesis and leukemia is missing. DUBs are poorly represented in in vivo published screens (Sertorio et al, 2017;Wang et al, 2012) and in vitro functional approaches for DUBs in cancer cell lines were hypothesis driven (Nishi et al, 2014).…”