SOD1is a synthetic lethal target inPPM1D-mutant leukemia cells

  1. Linda Zhang
  2. Joanne I. Hsu
  3. Etienne D. Braekeleer
  4. Chun-Wei Chen
  5. Tajhal D. Patel
  6. Alejandra G. Martell
  7. Anna G. Guzman
  8. Katharina Wohlan
  9. Sarah M. Waldvogel
  10. Hidetaka Urya
  11. Ayala Tovy
  12. Elsa Callen
  13. Rebecca Murdaugh
  14. Rosemary Richard
  15. Sandra Jansen
  16. Lisenka Vissers
  17. Bert B.A. de Vries
  18. Andre Nussenzweig
  19. Shixia Huang
  20. Cristian Coarfa
  21. Jamie N. Anastas
  22. Koichi Takahashi
  23. George Vassiliou
  24. Margaret A. Goodell
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Abstract

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase, Mg2+/Mn2+ dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications ofPPM1Dare found across several human cancers making it a relevant pharmacologic target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies ofPPM1D,uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress inPPM1D-mutant cells. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress inPPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy againstPPM1D-mutant cancers.

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