BRCA1 Promoter Methylation Is Linked to Defective Homologous Recombination Repair and Elevated miR-155 to Disrupt Myeloid Differentiation in Myeloid Malignancies

• Published in: Clinical cancer research Vol. 25; no. 8; pp. 2513 - 2522
• Main Authors: Poh, Weijie, Dilley, Robert L, Moliterno, Alison R, Maciejewski, Jaroslaw P, Pratz, Keith W, McDevitt, Michael A, Herman, James G
• Format: Journal Article
• Language: English
• Published: United States 15.04.2019
• Subjects: Adult; Aged; BRCA1 Protein - genetics; Cell Differentiation - genetics; Cell Survival - drug effects; DNA Methylation; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Leukemic - drug effects; Gene Silencing; Humans; Leukemia, Myeloid - genetics; Leukemia, Myeloid - pathology; Male; MicroRNAs - genetics; Middle Aged; Neoplasm Grading; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Promoter Regions, Genetic; Recombinational DNA Repair
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0179

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