Abstract 4025: Evaluation of homologous recombination (HR) genes in myeloproliferative neoplasms (MPNs) suggests BRCA1 as a potential biomarker for sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition and disease progression
Authors: Poh Weijie , Dilley Robert , Pratz Keith W. , McDevitt Michael A. , Herman James G. 
Published: August 2012

Myeloproliferative neoplasms (MPNs) present with excessive production of terminally differentiated blood cells derived from myeloid progenitor cells. 5-10% of Philadelphia (Ph)-negative MPNs, which include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), may eventually progress to acute myeloid leukemia (AML) with poor outcome. The lack of curative results with conventional therapy demonstrates an urgent need to identify pathways perturbed in MPNs which can be targeted. Previously, complete responses were observed in MPN patients in a trial combining poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 with carboplatin and topotecan which was associated with in vitro PARP inhibitor sensitivity (McDevitt et al., ASH 2011). To identify patients who will be sensitive to PARP inhibition, we investigated mechanisms underlying this favorable response. PARP inhibitors block repair of DNA single stand breaks, allowing these lesions to persist. The ensuing increase in DNA double stranded breaks (DSBs) cannot be repaired in cells defective in DNA homologous recombination (HR) repair and results in an exquisite death response of the malignant clone. Previously, we have observed using SNP-A arrays that MPNs have frequent deletions including genes involved in repairing DNA DSBs and cross-links: 13q (BRCA2), 9q (FANCC) and 11p (FANCF) (McDevitt et al., ASH 2011). In this study, we examined the prevalence of inactivation in HR repair genes (BRCA1, BRCA2, Fanconi Anemia genes, ATR, ATM, BLM) via epigenetic silencing in MPN and AML patients using methylation-specific PCR (MSP). BRCA1 quantitative MSP (qMSP) revealed promoter hypermethylation in 9% of 59 MPN patients which associated with decreased BRCA1 transcript. BRCA1 methylation was also observed in AML, and additional samples will be examined to clarify the role of epigenetic silencing in disease progression. Hypermethylation of FANCC (3%) and FANCL (3%) was observed in 30 AML samples at low frequencies, and has not been observed in the MPN samples examined thus far. Ongoing studies include SNP arrays to determine if epigenetic silencing complements allelic loss to generate HR repair defects, DNA damage foci formation assays with PARP inhibition to investigate functional defects in HR repair in primary cells isolated from patients in the ABT-888 trial. In addition, karyotypic profiles will be investigated to determine if complex cytogenetics are associated with repressed HR repair. In addition to studying how defects in HR repair, either via promoter methylation or allelic loss, contribute to disease pathogenesis, our studies will also determine if epigenetic silencing of HR genes can be used to identify a subpopulation of MPN patients that will respond favorably to PARP inhibition.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4025. doi:1538-7445.AM2012-4025