Exploiting Synthetic Lethality between Germline BRCA1 Haploinsufficiency and PARP Inhibition in JAK2V617F-Positive Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., ). We investigated the th...

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Published in:	International journal of molecular sciences Vol. 24; no. 24; p. 17560
Main Authors:	Bermes, Max, Rodriguez, Maria Jimena, de Toledo, Marcelo Augusto Szymanski, Ernst, Sabrina, Müller-Newen, Gerhard, Brümmendorf, Tim Henrik, Chatain, Nicolas, Koschmieder, Steffen, Baumeister, Julian
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 16-12-2023
Subjects:	Apoptosis BRCA1 BRCA1 Protein - genetics Breast cancer Cell cycle Cell growth DNA DNA damage Flow cytometry Germ Cells Haploinsufficiency Humans Interferon interferon-alpha Interferon-alpha - pharmacology Kinases Medical prognosis Metabolism Mortality MPN Mutation Myeloproliferative Disorders - drug therapy Myeloproliferative Disorders - genetics myeloproliferative neoplasms Neoplasms - drug therapy olaparib Ovarian cancer Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Recombinational DNA Repair Stem cells Synthetic Lethal Mutations Tumors myeloproliferative neoplasms IFNα haploinsufficiency homologous recombination repair olaparib synthetic lethality interferon-alpha MPN BRCA1 DNA repair
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Summary:	Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., ). We investigated the therapeutic potential of targeting haploinsufficiency alongside the V617F driver mutation. We assessed the efficacy of combining the PARP inhibitor olaparib with interferon-alpha (IFNα) in CRISPR/Cas9-engineered V617F-positive 32D cells. Olaparib treatment induced a higher number of DNA double-strand breaks, as demonstrated by γH2AX analysis through Western blot ( = 0.024), flow cytometry ( = 0.013), and confocal microscopy ( = 0.071). RAD51 foci formation was impaired in cells compared to cells, indicating impaired homologous recombination repair due to haploinsufficiency. Importantly, olaparib enhanced apoptosis while diminishing cell proliferation and viability in cells compared to cells. These effects were further potentiated by IFNα. Olaparib induced interferon-stimulated genes and increased endogenous production of IFNα in cells. These responses were abrogated by STING inhibition. In conclusion, our findings suggest that the combination of olaparib and IFNα presents a promising therapeutic strategy for MPN patients by exploiting the synthetic lethality between germline mutations and the V617F MPN driver mutation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms242417560