CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:34 |
|---|---|
| Enthalten in: |
Leukemia - 34(2020), 6 vom: 23. Juni, Seite 1599-1612 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Quijada-Álamo, Miguel [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 07.10.2020 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41375-020-0714-3 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM305715682 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM305715682 | ||
| 003 | DE-627 | ||
| 005 | 20231225121803.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41375-020-0714-3 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1019.xml |
| 035 | |a (DE-627)NLM305715682 | ||
| 035 | |a (NLM)31974435 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Quijada-Álamo, Miguel |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.10.2020 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Phthalazines |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a Piperidines |2 NLM | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a ibrutinib |2 NLM | |
| 650 | 7 | |a 1X70OSD4VX |2 NLM | |
| 650 | 7 | |a PARP1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.4.2.30 |2 NLM | |
| 650 | 7 | |a Poly (ADP-Ribose) Polymerase-1 |2 NLM | |
| 650 | 7 | |a EC 2.4.2.30 |2 NLM | |
| 650 | 7 | |a ATM protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Ataxia Telangiectasia Mutated Proteins |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a BCR protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-bcr |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Adenine |2 NLM | |
| 650 | 7 | |a JAC85A2161 |2 NLM | |
| 650 | 7 | |a olaparib |2 NLM | |
| 650 | 7 | |a WOH1JD9AR8 |2 NLM | |
| 700 | 1 | |a Hernández-Sánchez, María |e verfasserin |4 aut | |
| 700 | 1 | |a Alonso-Pérez, Verónica |e verfasserin |4 aut | |
| 700 | 1 | |a Rodríguez-Vicente, Ana E |e verfasserin |4 aut | |
| 700 | 1 | |a García-Tuñón, Ignacio |e verfasserin |4 aut | |
| 700 | 1 | |a Martín-Izquierdo, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Hernández-Sánchez, Jesús María |e verfasserin |4 aut | |
| 700 | 1 | |a Herrero, Ana B |e verfasserin |4 aut | |
| 700 | 1 | |a Bastida, José María |e verfasserin |4 aut | |
| 700 | 1 | |a San Segundo, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Gruber, Michaela |e verfasserin |4 aut | |
| 700 | 1 | |a García, Juan Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Yin, Shanye |e verfasserin |4 aut | |
| 700 | 1 | |a Ten Hacken, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Benito, Rocío |e verfasserin |4 aut | |
| 700 | 1 | |a Ordóñez, José Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Catherine J |e verfasserin |4 aut | |
| 700 | 1 | |a Hernández-Rivas, Jesús María |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Leukemia |d 1989 |g 34(2020), 6 vom: 23. Juni, Seite 1599-1612 |w (DE-627)NLM012593788 |x 1476-5551 |7 nnns |
| 773 | 1 | 8 | |g volume:34 |g year:2020 |g number:6 |g day:23 |g month:06 |g pages:1599-1612 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41375-020-0714-3 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 34 |j 2020 |e 6 |b 23 |c 06 |h 1599-1612 | ||