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Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice

Voisset, Edwige, Moravcsik, Eva, Stratford, Eva W., Jaye, Amie, Palgrave, Christopher, Hills, Robert K., Salomoni, Paolo, Kogan, Scott C., Solomon, Ellen and Grimwade, David (2017) Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice Blood.

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Pml nuclear body disruption cooperates in APL pathogenesis and impairs DNA damage repair pathways in mice.pdf - Accepted version Manuscript
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Abstract

A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of PML nuclear bodies (NBs) mediated by the PML-RARα oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by two point mutations (C62A/C65A) in the Pml RING domain. While no leukemias developed in PmlC62A/C65A mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period. Additionally, we found that response to targeted therapy with all-trans retinoic acid (ATRA) in vivo was dependent on NB integrity. PML-RARα is recognized to be insufficient for development of APL, requiring acquisition of cooperating mutations. We therefore investigated whether NB disruption might be mutagenic. Compared to wild-type cells, primary PmlC62A/C65A cells exhibited increased sister-chromatid exchange and chromosome abnormalities. Moreover, functional assays showed impaired homologous recombination (HR) and non-homologous end-joining (NHEJ) repair pathways, with defective localization of Brca1 and Rad51 to sites of DNA damage. These data directly demonstrate that Pml NBs are critical for DNA damage responses, and suggest that Pml NB disruption is a central contributor to APL pathogenesis.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
NameEmailORCID
Voisset, EdwigeUNSPECIFIEDUNSPECIFIED
Moravcsik, EvaUNSPECIFIEDUNSPECIFIED
Stratford, Eva W.UNSPECIFIEDUNSPECIFIED
Jaye, AmieUNSPECIFIEDUNSPECIFIED
Palgrave, Christopherc.palgrave@surrey.ac.ukUNSPECIFIED
Hills, Robert K.UNSPECIFIEDUNSPECIFIED
Salomoni, PaoloUNSPECIFIEDUNSPECIFIED
Kogan, Scott C.UNSPECIFIEDUNSPECIFIED
Solomon, EllenUNSPECIFIEDUNSPECIFIED
Grimwade, DavidUNSPECIFIEDUNSPECIFIED
Date : 30 November 2017
Identification Number : 10.1182/blood-2017-07-794784
Copyright Disclaimer : Copyright © 2017 American Society of Hematology
Depositing User : Clive Harris
Date Deposited : 13 Dec 2017 09:48
Last Modified : 13 Dec 2017 09:48
URI: http://epubs.surrey.ac.uk/id/eprint/845239

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