CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition

Leukemia. 2020 Jun;34(6):1599-1612. doi: 10.1038/s41375-020-0714-3. Epub 2020 Jan 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Ataxia Telangiectasia Mutated Proteins / genetics*
  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Chromosome Deletion
  • Chromosomes, Human, Pair 11 / genetics
  • Drug Synergism
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Mice
  • Mutagenesis, Site-Directed / methods*
  • Mutation
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcr / antagonists & inhibitors
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • BCR protein, human
  • Proto-Oncogene Proteins c-bcr
  • olaparib