RT Journal Article
T1 CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition
A1 Quijada Álamo, Miguel
A1 Hernández Sánchez, María
A1 Alonso Pérez, Verónica
A1 Rodríguez Vicente, Ana E.
A1 García Tuñón, Ignacio
A1 Martín Izquierdo, Marta
A1 Hernández Sánchez, Jesús María
A1 Herrero, Ana B.
A1 Bastida, José María
A1 San Segundo, Laura
A1 Gruber, Michaela
A1 García, Juan Luis
A1 Yin, Shanye
A1 Hacken, Elisa ten
A1 Benito, Rocío
A1 Ordóñez, José Luis
A1 Wu, Catherine J.
A1 Hernández-Rivas, Jesús María
AB 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
PB Nature Publishing Group
SN 0887-6924
SN 1476-5551
YR 2020
FD 2020-01-23
LK https://hdl.handle.net/20.500.14352/110927
UL https://hdl.handle.net/20.500.14352/110927
LA eng
NO Quijada-Álamo, Miguel, et al. «CRISPR/Cas9-Generated Models Uncover Therapeutic Vulnerabilities of Del(11q) CLL Cells to Dual BCR and PARP Inhibition». Leukemia, vol. 34, n.o 6, junio de 2020, pp. 1599-612. DOI.org (Crossref), https://doi.org/10.1038/s41375-020-0714-3.
NO Fondo de Investigaciones Sanitarias
NO Instituto de Salud Carlos III
NO European Commission-ERC
NO Consejería de Educación, Junta de Castilla y León
NO Proyectos de Investigación del SACYL
NO Fundación Memoria Don Samuel Solórzano Barruso
NO Red Temática de Investigación Cooperativa en Cáncer
NO Centro de Investigación Biomédica en Red de Cáncer
DS Docta Complutense
RD 16 abr 2025