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PML nuclear body disruption impairs DNA double-strand break sensing and repair in APL

A di Masi1,2, D Cilli1, F Berardinelli1

  • 1Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, Rome 00146, Italy.

Cell Death & Disease
|July 30, 2016
PubMed

Insights

Acute promyelocytic leukemia (APL) involves disrupted DNA double-strand break (DSB) repair within promyelocytic leukemia nuclear bodies (PML-NBs). The PML-RARα oncoprotein impairs this repair, contributing to APL leukemogenesis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • DNA double-strand break (DSB) repair proteins localize to promyelocytic leukemia nuclear bodies (PML-NBs).
  • PML-NB disruption is central to acute promyelocytic leukemia (APL) pathogenesis.
  • All-trans-retinoic acid (RA) treatment in APL clears PML-RARα, restoring PML-NBs and inducing differentiation.

Purpose of the Study:

  • Investigate the role of PML-RARα oncoprotein and PML-NB integrity in DSB response during APL.
  • Clarify the impact of PML-NB disruption on leukemogenesis and tumor suppression in APL.
  • Determine how RA treatment affects DSB repair in APL.

Main Methods:

  • Analysis of γ-H2AX phosphorylation in primary APL blasts.
  • Studying ionizing radiation (IR)-induced DSB response in APL cells and a mouse model before and after RA treatment.
  • Assessing the kinetics of γ-H2AX and 53BP1 foci, and ATM pathway activation (H2AX, NBN, CHK2).

Main Results:

  • APL blasts exhibit high γ-H2AX levels.
  • PML-NB disruption correlates with a delayed DSB response, evidenced by slower γ-H2AX/53BP1 foci clearance and impaired ATM pathway activation.
  • PML-RARα-induced disruption of PML-NB integrity affects IR-induced DSB response in vivo in an APL mouse model.

Conclusions:

  • Oncoprotein-dependent PML-NB disruption impairs DNA damage response (DDR) in APL.
  • Impaired DDR is proposed as an early event in APL tumorigenesis.
  • Restoring PML-NB integrity via RA treatment may be crucial for therapeutic strategies in APL.

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