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 language | English (US) |
|---|---|
| Pages (from-to) | 2513-2522 |
| Number of pages | 10 |
| Journal | Clinical Cancer Research |
| Volume | 25 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 15 2019 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
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.
PY - 2019/4/15
Y1 - 2019/4/15
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.
UR - http://www.scopus.com/inward/record.url?scp=85064729278&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064729278&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-0179
DO - 10.1158/1078-0432.CCR-18-0179
M3 - Article
C2 - 30692098
AN - SCOPUS:85064729278
VL - 25
SP - 2513
EP - 2522
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 8
ER -