Abstract
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.
Highlights
Acute myeloid leukemia (AML) is a hematopoietic malignancy defined by ineffective hematopoiesis, defects in myeloid differentiation, and an accumulation of myeloid blasts in the bone marrow (BM) and peripheral blood (PB) of patients
AML exhibits high Ubiquitin-specific peptidase 15 (USP15) expression compared to other tumor types and normal hematopoietic cells Previously we reported that the del(5q) MDS gene TIFAB controls hematopoietic stem and progenitor cells (HSPCs) functions under stressed conditions through direct interaction and regulation of USP15 function [26, 27, 34, 35]
USP15 transcripts are readily expressed within many tumor types, their expression is remarkably higher in AML samples (Fig. 1A)
Summary
Acute myeloid leukemia (AML) is a hematopoietic malignancy defined by ineffective hematopoiesis, defects in myeloid differentiation, and an accumulation of myeloid blasts in the bone marrow (BM) and peripheral blood (PB) of patients. Leukemia cells persist despite elevated levels of ROS, likely by upregulating compensatory pathways [7] Transcription factors such as FOXOs, NRF2, NF-κB, and HIF1-α are regulated by ROS, as are glycolytic enzymes, mitochondrial transporters, p38MAPK, and mTOR pathways [8,9,10,11,12]. ROS and metabolic processes are intricately intertwined in hematopoiesis and leukemic cells leverage these mechanisms to drive cell survival programs despite oxidative stress. This co-opted network of malignant hematopoietic cell metabolism and redox homeostasis represents a target-rich space for selectively depleting leukemic cells [13]
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