Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers

Francesca Cottini, Teru Hideshima, Chunxiao Xu, Martin Sattler, Martina Dori, Luca Agnelli, Elisa Ten Hacken, Maria Teresa Bertilaccio, Elena Antonini, Antonino Neri, Maurilio Ponzoni, Magda Marcatti, Paul G. Richardson, Ruben Carrasco, Alec C. Kimmelman, Kwok Kin Wong, Federico Caligaris-Cappio, Giovanni Blandino, W. Michael Kuehl, Kenneth C. AndersonGiovanni Tonon

Research output: Contribution to journalArticlepeer-review

Abstract

Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.

Original languageEnglish
Pages (from-to)599-606
Number of pages8
JournalNature Medicine
Volume20
Issue number6
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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