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

Abstract

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., BRCA1). We investigated the therapeutic potential of targeting BRCA1 haploinsufficiency alongside the JAK2V617F driver mutation. We assessed the efficacy of combining the PARP inhibitor olaparib with interferon-alpha (IFNα) in CRISPR/Cas9-engineered Brca1+/− Jak2V617F-positive 32D cells. Olaparib treatment induced a higher number of DNA double-strand breaks, as demonstrated by γH2AX analysis through Western blot (p = 0.024), flow cytometry (p = 0.013), and confocal microscopy (p = 0.071). RAD51 foci formation was impaired in Brca1+/− cells compared to Brca1+/+ cells, indicating impaired homologous recombination repair due to Brca1 haploinsufficiency. Importantly, olaparib enhanced apoptosis while diminishing cell proliferation and viability in Brca1+/− cells compared to Brca1+/+ cells. These effects were further potentiated by IFNα. Olaparib induced interferon-stimulated genes and increased endogenous production of IFNα in Brca1+/− 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 BRCA1 mutations and the JAK2V617F MPN driver mutation.

Cancer: A Multifaceted Enemy and the Precision Oncology Response

“…PARP Inhibition and Immune Response in Myeloproliferative Neoplasms (MPNs): Bermes and colleagues explored the combined effects of olaparib, a PARP inhibitor that disrupts DNA repair, with interferon-alpha (IFNα), which is known for its antitumor immunity [ 5 ]. Their research sheds light on the potential of exploiting the synthetic lethality between genetic anomalies in MPN (JAK2V617F mutation and BRCA1 haploinsufficiency) and enhancing the immune response.…”

“…Chromosomal Instability (CIN) and its clinical implications in Breast Cancer: Camargo-Herrera and colleagues conducted a pilot study investigating the role of CIN and clonal heterogeneity in luminal B breast cancer [2]. Bermes and colleagues explored the combined effects of olaparib, a PARP inhibitor that disrupts DNA repair, with interferon-alpha (IFNα), which is known for its antitumor immunity [5]. Their research sheds light on the potential of exploiting the synthetic lethality between genetic anomalies in MPN (JAK2V617F mutation and BRCA1 haploinsufficiency) and enhancing the immune response.…”