Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma
- Author(s)
- Davies, N; Francis, T; Oldreive, C; Azam, M; Wilson, J; Byrd, PJ; Burley, M; Sharma-Oates, A; Keane, P; Alatawi, S; Higgs, MR; Rudzki, Z; Ibrahim, M; Perry, T; Agathaggelou, A; Hewitt, AM; Smith, E; Bonifer, C; O'Connor, M; Forment, JV; Murray, PG; Fennell, E; Kelly, G; Chang, C; Stewart, GS; Stankovic, T; Kwok, M; Taylor, AM;
- Journal Title
- Haematologica
- Publication Type
- Jun 6 epub ahead of print
- Abstract
- Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied ribonucleic acid (RNA)-seq and genome-scale loss-offunction clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations. Atm-/-nu-/-lymphomas, which phenotypically resemble either activated B-cell-like or germinal center Bcell-like DLBCL, harbor a complex karyotype, and are characterized by MYC pathway activation. In Atm-/-nu-/-lymphomas, we discovered nucleotide biosynthesis as a MYCdependent cellular vulnerability that can be targeted through the synergistic nucleotidedepleting actions of mycophenolate mofetil (MMF) and the WEE1 inhibitor, adavosertib (AZD1775). The latter is mediated through a synthetically lethal interaction between RRM2 suppression and MYC dysregulation that results in replication stress overload in Atm-/-nu-/-lymphoma cells. Validation in cell line models of human DLBCL confirmed the broad applicability of nucleotide depletion as a therapeutic strategy for MYC-driven DLBCL independent of ATM mutation status. Our findings extend current understanding of lymphomagenic mechanisms underpinning ATM loss and highlight nucleotide metabolism as a targetable therapeutic vulnerability in MYC-driven DLBCL.
- Publisher
- Ferrata-Storti Foundation
- Research Division(s)
- Blood Cells And Blood Cancer
- PubMed ID
- 38841800
- Publisher's Version
- https://doi.org/10.3324/haematol.2023.284404
- Open Access at Publisher's Site
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Creation Date: 2024-06-24 11:29:50
Last Modified: 2024-06-24 11:42:31