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

Edwige Voisset, Eva Moravcsik, Eva W. Stratford, Amie Jaye, Christopher J. Palgrave, Robert K. Hills, Paolo Salomoni, Scott C. Kogan, Ellen Solomon and David Grimwade

Key points

  • A novel mouse model elucidates the impact of Pml NB disruption on APL pathogenesis and response to targeted therapy.

  • The mode of action of this disruption appears to be via the perturbation of the NHEJ and HR pathways.

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.

  • Submitted July 5, 2017.
  • Accepted November 26, 2017.