Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma.

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
08 Feb 2024

Historique:

received: 29 07 2022

accepted: 18 01 2024

medline: 9 2 2024

pubmed: 9 2 2024

entrez: 8 2 2024

Statut: epublish

Résumé

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.

Identifiants

DOI: 10.1038/s41467-024-45350-8 PMID: 38331987

pubmed: 38331987

doi: 10.1038/s41467-024-45350-8

pii: 10.1038/s41467-024-45350-8

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

1203

Subventions

Organisme : U.S. Department of Health & Human Services | NIH | Center for Scientific Review (NIH Center for Scientific Review)

ID : R01CA222253

Informations de copyright

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