USP15 Deubiquitinase Safeguards Hematopoiesis and Genome Integrity in Hematopoietic Stem Cells and Leukemia Cells

Berk, Paul van den; Lancini, Cesare; Serresi, Michela; Sánchez-Bailón, María Pilar; Hulsman, Danielle; Pritchard, Colin C.; Song, Ji‐Ying; Schmitt, Matthias Jürgen; Tanger, Ellen; Popp, Oliver; Mertins, Philipp; Huijbers, Ivo J.; Jacobs, Heinz; Lohuizen, Maarten van; Gargiulo, Gaetano; Citterio, Elisabetta

doi:10.1016/j.celrep.2020.108533

Cited by 15 publications

(22 citation statements)

References 92 publications

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“…USP15 has been functionally implicated in various cancers [305][306][307][308], but only recent work uncovered its role in myeloid leukemia [273,309]. In our study, USP15 was found overexpressed in human blood cancers, with the highest expression in AML.…”

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 52%

“…While USP15 regulates oncogenic pathways, such as TP53 [310,311] and TGF-b signaling [307], in AML cells we provided evidence that USP15 functionally interacts with FUS, stabilizing its protein levels [273]. As discussed above, FUS fusion proteins are involved in AML [76] and promote HSC self-renewal [312].…”

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 52%

“…Finally, consistently with a crucial role of DDR in HSC self-renewal [193,199,270], an increasing number of DUBs impacting on DDR have been implicated in HSC maintenance [271]. These include USP1 [272], USP3 [196], USP15 [273], USP16 [274,275], and MYSM1 [276,277]. Here, we will focus on recent findings on DDRrelated DUBs in myeloid malignancies and briefly discuss a few examples of emerging targeting opportunities of DUB enzymes.…”

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 99%

“…USP15, together with USP4 and USP11, form a closely related family of USPs, linked to DSB repair [273,[300][301][302][303][304][305][306]. They are all expressed in early hematopoietic progenitors [196] and we recently scored them as hits in an in vivo shRNA screen for DUBs in mouse HSPCs, implicating these enzymes in HSC homeostasis [273]. Indeed, USP15 was validated as a critical DUB in HSC function and genome maintenance in Usp15 knockout mice [273].…”

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 99%

“…In our study, USP15 was found overexpressed in human blood cancers, with the highest expression in AML. Furthermore, USP15 depletion impaired the viability of human CML and AML cell lines (M4-11, Kasumi-1) and increased their sensitivity to clastogens, including the crosslinking agent mitomycin C [273].…”

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 99%

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Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Barabino

Citterio

2021

Cancers

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Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.

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Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 52%

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 52%

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 99%

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 99%

Section: Deubiquitinating Enzymes In Hscs Genome Stabilitymentioning

confidence: 99%

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Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Barabino

Citterio

2021

Cancers

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Deubiquitinases at the interplay between hematopoietic stem cell aging and myelodysplastic transformation

Citterio,

Ronchi

2024

FEBS Letters

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The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia

et al. 2021

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Ubiquitin-specific peptidase 15 (USP15) is a deubiquitinating enzyme implicated in critical cellular and oncogenic processes. We report that USP15 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) as compared to normal hematopoietic progenitor cells. This high expression of USP15 in AML correlates with KEAP1 protein and suppression of NRF2. Knockdown or deletion of USP15 in human and mouse AML models significantly impairs leukemic progenitor function and viability and de-represses an antioxidant response through the KEAP1-NRF2 axis. Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function. In contrast, USP15 is dispensable for human and mouse normal hematopoietic cells in vitro and in vivo. A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML. Based on these findings, we report that USP15 drives AML cell function, in part, by suppressing a critical oxidative stress sensor mechanism and permitting an aberrant redox state. Furthermore, we postulate that inhibition of USP15 activity with small molecule inhibitors will selectively impair leukemic progenitor cells by re-engaging homeostatic redox responses while sparing normal hematopoiesis.

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USP15 Deubiquitinase Safeguards Hematopoiesis and Genome Integrity in Hematopoietic Stem Cells and Leukemia Cells

Cited by 15 publications

References 92 publications

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Deubiquitinases at the interplay between hematopoietic stem cell aging and myelodysplastic transformation

The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia

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