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USP20, a Super-enhancer Regulated Gene, Promotes Acute Myeloid Leukemia Progression through CTNNB1 Deubiquitination

ABSTRACT: Acute Myeloid Leukemia (AML) is a heterogeneous hematologic malignancy driven by genetic and epigenetic alterations, where super-enhancers (SEs) play key oncogenic roles, representing promising therapeutic targets in AML. Through H3K27ac ChIP-seq profiling of 7 AML cell lines and 13 primary samples, we identified USP20 as the deubiquitinase that most frequently associated with super-enhancers. Public database analysis confirmed USP20 overexpression in AML and its correlation with adverse prognosis. Genetic knockdown of USP20 via shRNA significantly induced apoptosis and suppressed proliferation in AML cells in vitro, while in vivo depletion of USP20 attenuated leukemia development and improved overall survival. AS1517499, a novel USP20 inhibitor identified via virtual screening, recapitulated these anti-leukemic effects in vitro and in vivo with low toxicity. Mechanistically, USP20 interacts with CTNNB1 and stabilizes the CTNNB1 protein via deubiquitination. CUT&Tag analysis indicated that USP20 co-localizes with CTNNB1 on the genome, where they jointly regulate target genes in AML. Collectively, our study identified USP20 as a super-enhancer-regulated oncogene maintaining AML cell survival and proliferation through CTNNB1 stabilization. Pharmacologic targeting of USP20 with AS1517499 presents a promising therapeutic strategy targeting the SE-USP20- CTNNB1 axis.

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ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Fang Fang

LAB HEAD: Jia Cheng

PROVIDER: PXD066445 | Pride | 2026-03-16

REPOSITORIES: Pride

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Project description:Background: A fundamental hallmark of cancer cells is their ability to sustain proliferative signaling and cell survival, reflected in a cellular chemotherapy response that is poorly understood. We questioned whether chemotherapy modulated phospho-signaling at 4 and 24 h in vivo could provide information about long-term survival in acute myeloid leukemia (AML), and if the signaling response to therapy was more informative than analysis at time of diagnosis. Methods: Peripheral blood was collected from 32 younger AML patients (age 16-74 years), before, 4- and 24 hours after start of induction chemotherapy. Samples were analyzed by 36-dimensional mass cytometry for assessment of alterations in immunophenotypes and intracellular signaling using unsupervised and supervised machine learning approaches. Results were validated by RNA sequencing and mass spectrometry proteomics (Super SILAC). Targeted sequencing was used to characterize patient samples for recurrent AML mutations. Drug sensitivity and resistance testing ex vivo was compared to activation of relevant signal transduction pathways and mutational profile. Findings: 5-year patient survival was accurately predicted in the leukemic cell population at 24 hours after therapy onset by phospho-proteins p-ERK1/2 (T202/Y204) and p-p38 (T180/Y182). RNA sequencing showed induction of MAPK target gene expression and the AP-1 transcription complex in patients with high p-ERK1/2. Super-SILAC proteomics confirmed an increase in the abundance of p38 prime target MAPKAPK2(MK2) 24 hours after start of induction therapy. Ex vivo drug sensitivity testing demonstrated high sensitivity to MEK inhibitors in the patient cells with high p-ERK1/2 measured at diagnosis or 24 hours after start of chemotherapy. Interpretation: Early single cell signaling response to chemotherapy provided precise prognostic information independent of stratification by genetics. We propose that early functional measurement of chemotherapy-potentiated MAPK pathway signaling could identify non-responders to intensive chemotherapy allowing precise treatment adjustment.

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USP20, a Super-enhancer Regulated Gene, Promotes Acute Myeloid Leukemia Progression through CTNNB1 Deubiquitination

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