ArticleLeukemia2020
CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition.
Article in Leukemia, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 37 citations in OpenAlex.
- ZNF292 mutations impair RNA and protein biosynthesis defining an adverse prognostic subset in early-stage chronic lymphocytic leukemia.Biomarker research · 2026Article
- ZMYM3 mutations modulate histone acetylation and cooperate with NOTCH1 mutations in chronic lymphocytic leukemia.Blood advances · 2026Article
- CBX2 phase-separation contributes to homologous recombination repair and drug resistance in ovarian cancer.Cell death & disease · 2026Article
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- Advances in RNA-based cancer therapeutics: pre-clinical and clinical implications.Molecular cancer · 2025Review
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- Identification of UBA7 expression downregulation in myelodysplastic neoplasm with SF3B1 mutations.Scientific reports · 2025Article
- SAMHD1 dysfunction impairs DNA damage response and increases sensitivity to PARP inhibition in chronic lymphocytic leukemia.Scientific reports · 2025Article
- The molecular map of CLL and Richter's syndrome.Seminars in hematology · 2024Review
- Mouse models of chronic lymphocytic leukemia and Richter transformation: what we have learnt and what we are missing.Frontiers in immunology · 2024Review
- Chromosome-level genome editing uncovers aneuploidy addiction in cancer.Cell reports methods · 2023Article
- Robust CRISPR-Cas9 Genetic Editing of Primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells.HemaSphere · 2023Article
- Review
- Review
- [The correlation of CD49d expression pattern with molecular genetics and hotspot gene mutants in patients with chronic lymphocytic leukemia].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2022Article
- Review
- Review
- From Descriptive to Functional Genomics of Leukemias Focusing on Genome Engineering Techniques.International journal of molecular sciences · 2021Review
- B cell receptor (BCR) guided mechanotransduction: Critical hypothesis to instruct SARS-CoV-2 specific B cells to trigger proximal signalling and antibody reshaping.Medical hypotheses · 2021Article
- Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression.Blood cancer journal · 2021Article
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 3 countries.
Funding
Abstract
The deletion of 11q (del(11q)) invariably comprises ATM gene in chronic lymphocytic leukemia (CLL). Concomitant mutations in this gene in the remaining allele have been identified in 1/3 of CLL cases harboring del(11q), being the biallelic loss of ATM associated with adverse prognosis. Although the introduction of targeted BCR inhibition has significantly favored the outcomes of del(11q) patients, responses of patients harboring ATM functional loss through biallelic inactivation are unexplored, and the development of resistances to targeted therapies have been increasingly reported, urging the need to explore novel therapeutic approaches. Here, we generated isogenic CLL cell lines harboring del(11q) and ATM mutations through CRISPR/Cas9-based gene-editing. With these models, we uncovered a novel therapeutic vulnerability of del(11q)/ATM-mutated cells to dual BCR and PARP inhibition. Ex vivo studies in the presence of stromal stimulation on 38 CLL primary samples confirmed a synergistic action of the combination of olaparib and ibrutinib in del(11q)/ATM-mutated CLL patients. In addition, we showed that ibrutinib produced a homologous recombination repair impairment through RAD51 dysregulation, finding a synergistic link of both drugs in the DNA damage repair pathway. Our data provide a preclinical rationale for the use of this combination in CLL patients with this high-risk cytogenetic abnormality.
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