Genome-scale clustered regularly interspaced short palindromic repeats screen identifies nucleotide metabolism as an actionable therapeutic vulnerability in diffuse large B-cell lymphoma

Davies, N; Agathanggelou, A; 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; Hewitt, AM; Smith, E; Bonifer, C; O&#39;Connor, M; Forment, JV; Murray, PG; Fennell, E; Kelly, G; Chang, C; Stewart, GS; Stankovic, T; Kwok, M; Taylor, AM

Author(s): Davies, N; Agathanggelou, A; 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; 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;
Details: Publication Year 2024-12-01,Volume 109,Issue #12,Page 3989-4006
Journal Title: Haematologica
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 RNA sequencing and genome-scale loss-of-function 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 B-cell-like DLBCL, harbor a complex karyotype, and are characterized by MYC pathway activation. In Atm-/-nu-/- lymphomas, we discovered nucleotide biosynthesis as a MYC-dependent cellular vulnerability that can be targeted through the synergistic nucleotide-depleting 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
Keywords: *Lymphoma, Large B-Cell, Diffuse/genetics/metabolism/pathology; Mice; Animals; Humans; *Ataxia Telangiectasia Mutated Proteins/genetics/metabolism; Nucleotides/metabolism; Clustered Regularly Interspaced Short Palindromic Repeats; Mice, Knockout; Disease Models, Animal; CRISPR-Cas Systems; Cell Line, Tumor
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: https://doi.org/ 10.3324/haematol.2023.284404
Terms of Use/Rights Notice: Refer to copyright notice on published article.
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Creation Date: 2024-06-24 11:29:50

Last Modified: 2024-12-05 10:41:47