Dataset Information

Inhibition of ADSS2-mediated de novo AMP biosynthesis resensitizes acute myeloid leukemia to BH3 mimetics

ABSTRACT: De novo purine synthesis is required to promote tumor growth; however, its role in therapy resistance remains elusive. Here, through a dynamic BH3-priming based CRISPR-Cas9 screen, we found that deletion of ADSS2, which encodes for an enzyme functioning in de novo AMP synthesis, re-sensitizes drug resistant acute myeloid leukemia (AML) cells to BH3 mimetics. Single-cell sequencing and metabolomics analyses reveal that high ADSS2 activity in leukemia samples including those with TP53 aberrations inversely correlates with venetoclax responsiveness. Further, we developed anADSS2 antagonist, exhibiting synergism with BH3 mimetics in preclinical AML models. Mechanistically, sensitization to BH3 mimetics mediated by ADSS targeting was associated with downregulated AMPK activity, which governs mitochondrial homeostasis. AMPK activity in resistant cells promotes mitophagy to eliminate damaged mitochondria upon BH3 mimetics treatment. These data demonstrate that AMP synthesis governs venetoclax resistance, and that combining ADSS targeting with BH3 mimetic treatment could represent a promising approach against AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280009 | GEO | 2025/11/21

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Ventoclax-based combinations are a new standard of care for patients with acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy, but not all patients respond to these treatments, and those who do may relapse. MDM2 inhibitors are promising therapeutics for treating TP53 wild-type tumors, including most de novo AML cases, but clinical trials have shown modest and variable clinical activity. Functional genomic data suggest that venetoclax and the MDM2 inhibitor, idasanutlin, may be ineffective against monocytic leukemia (FAB M4/M5) or leukemia cells with a high immune signature. We hypothesize upregulated myeloid transcription factors and enrichment of certain environmental cues that confer intrinsic and extrinsic drug resistance to these cells. We show that monocytic leukemia cells express a high level of CEBPB and CEBPB overexpression confers drug resistance to a broad range of BH3 mimetics, venetoclax combinations, and MDM2 inhibitors by downregulating CASP3, CASP6, BCL2, and p53 pathway targets, while upregulating MCL1, BCL2A1, and the NFKB/IL1/TNFA pathway. Moreover, leukemia monocytes can extrinsically protect leukemia blasts from venetoclax and MDM2 inhibition by secreting elevated IL1 and TNFA, which drive myelo/monocytic differentiation and upregulate inflammatory cytokines and receptors, including IL1/TNFA pathway in an autoregulatory loop. Remarkably, IL1A/IL1B and TNFA uniquely upregulate CEBPB expression in M4/M5 cells and protect them from apoptosis induced by venetoclax and MDM2 inhibitors. Conversely, TNFA treatment enhances extrinsic apoptosis in M0/M1 leukemia cells. Inhibitors of IRAK or MAPK14 (p38), which block IL1/TNFA signaling, showed synergistic cytotoxicity in M4/M5 AML when combined with venetoclax and idasanutlin. In summary, we described a targetable, positive feedback loop between CEBPB and IL1/TNFA in monocytic leukemia that drives intrinsic and extrinsic drug resistance to BCL2 and MDM2 inhibitors, offering promising therapeutic strategies to enhance treatment efficacy for monocytic leukemia.

Dataset Information

Inhibition of ADSS2-mediated de novo AMP biosynthesis resensitizes acute myeloid leukemia to BH3 mimetics

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets