BRCA1 promoter methylation is linked to defective homologous recombination repair and elevated miR-155 to disrupt myeloid differentiation in myeloid malignancies

Purpose: Defective homologous recombination (HR) has members of the HR pathway (BRCA2, ATM, ATR, FANC-been reported in multiple myeloid disorders, suggesting a A). In vitro BRCA1 knockdown increased sensitivity to PARP shared dysregulated pathway in these diverse malignancies. inhibition, and BRCA1 expression is inversely correlated Because targeting HR-defective cancers with PARP inhibi-with miR-155 expression, a finding reproduced in vitro with tion (PARPi) has yielded clinical benefit, improved under-BRCA1 knockdown. Increased miR-155 was associated with standing of HR defects is needed to implement this treat-PU.1 and SHIP1 repression, known myeloid differentiation ment modality. factors that are frequently downregulated during leukemic Experimental Design: We used an ex vivo irradiation-based transformation. assay to evaluate HR repair, HR gene promoter methylation, Conclusions: This study demonstrates frequent defective and mRNA expression in primary myeloid neoplastic cells. HR, associated with BRCA1 epigenetic silencing, in a broad In vitro BRCA1 gene silencing was achieved to determine the range of myeloid neoplasms. The increased prevalence of consequences on HR repair, sensitivity to PARPi, and expres-BRCA1 promoter methylation, resulting in repressed BRCA1, sion of miR-155, an oncogenic miRNA. may have an additional role in leukemogenesis by increasing Results: Impaired HR repair was frequently detected miR-155 expression, which then inhibits transcription factors in myeloid neoplasm samples (9/21, 43%) and was associated with normal myeloid differentiation. Further study linked to promoter methylation-mediated transcriptional of HR defects may facilitate the identification of HR-defective repression of BRCA1, which was not observed for other myeloid neoplasms sensitive to PARPi.