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

Weijie Poh, Robert L. Dilley, Alison R Moliterno, Jaroslaw P. Maciejewski, Keith Pratz, Michael A. McDevitt, James G. Herman

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2513-2522
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number8
DOIs
StatePublished - Apr 15 2019

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Recombinational DNA Repair
Homologous Recombination
Methylation
Neoplasms
BRCA1 Gene
Gene Silencing
Myeloid Cells
MicroRNAs
Epigenomics
Research Design
Transcription Factors
Down-Regulation
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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BRCA1 promoter methylation is linked to defective homologous recombination repair and elevated miR-155 to disrupt myeloid differentiation in myeloid malignancies. / Poh, Weijie; Dilley, Robert L.; Moliterno, Alison R; Maciejewski, Jaroslaw P.; Pratz, Keith; McDevitt, Michael A.; Herman, James G.

In: Clinical Cancer Research, Vol. 25, No. 8, 15.04.2019, p. 2513-2522.

Research output: Contribution to journalArticle

Poh, Weijie ; Dilley, Robert L. ; Moliterno, Alison R ; Maciejewski, Jaroslaw P. ; Pratz, Keith ; McDevitt, Michael A. ; Herman, James G. / BRCA1 promoter methylation is linked to defective homologous recombination repair and elevated miR-155 to disrupt myeloid differentiation in myeloid malignancies. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 8. pp. 2513-2522.
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T1 - BRCA1 promoter methylation is linked to defective homologous recombination repair and elevated miR-155 to disrupt myeloid differentiation in myeloid malignancies

AU - Poh, Weijie

AU - Dilley, Robert L.

AU - Moliterno, Alison R

AU - Maciejewski, Jaroslaw P.

AU - Pratz, Keith

AU - McDevitt, Michael A.

AU - Herman, James G.

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N2 - 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.

AB - 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.

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