Format

Send to:

Choose Destination
See comment in PubMed Commons below
Nat Med. 2014 Jun;20(6):599-606. doi: 10.1038/nm.3562. Epub 2014 May 11.

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

Author information

  • 11] Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
  • 2Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 31] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. [3] Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 4Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 5Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
  • 6Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • 7Laboratory of Lymphoid Malignancies, Division of Molecular Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 8Pathology Unit, Myeloma Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 9Department of Hematology-Oncology, Hematology and Bone Marrow Transplantation Unit, Myeloma Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 10Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
  • 111] Laboratory of Lymphoid Malignancies, Division of Molecular Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. [2] Università Vita-Salute San Raffaele, Milan, Italy. [3] MAGIC (Microenvironment and Genes in Cancers of the blood) Interdivisional Research Program, IRCCS San Raffaele Scientific Institute, Milan, Italy.
  • 12Translational Oncogenomic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
  • 13Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
  • 141] Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2].
  • 151] Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy. [2] Università Vita-Salute San Raffaele, Milan, Italy. [3] MAGIC (Microenvironment and Genes in Cancers of the blood) Interdivisional Research Program, IRCCS San Raffaele Scientific Institute, Milan, Italy. [4].

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.

PMID:
24813251
[PubMed - indexed for MEDLINE]
PMCID:
PMC4057660
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Write to the Help Desk