title: Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers.
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.
authors.affiliation: 1] 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cottini
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: 1] 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.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.affiliation: Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Dori
authors.affiliation: Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Agnelli
authors.affiliation: Laboratory of Lymphoid Malignancies, Division of Molecular Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: ten Hacken
authors.affiliation: Laboratory of Lymphoid Malignancies, Division of Molecular Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bertilaccio
authors.affiliation: Functional Genomics of Cancer Unit, Division of Molecular Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Antonini
authors.affiliation: Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Neri
authors.affiliation: Pathology Unit, Myeloma Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Department of Hematology-Oncology, Hematology and Bone Marrow Transplantation Unit, Myeloma Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Magda
authors.initials: M
authors.lastname: Marcatti
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Carrasco
authors.affiliation: Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Alec C
authors.initials: AC
authors.lastname: Kimmelman
authors.affiliation: 1] 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.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: 1] 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.
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.affiliation: Translational Oncogenomic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Kuehl
authors.affiliation: 1] Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. [2].
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: 1] 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].
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000704:Analysis of Variance; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D001897:Boronic Acids; D000069286:Bortezomib; D004249:DNA Damage / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D004317:Doxorubicin; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011719:Pyrazines; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001897:Boronic Acids; D000069286:Bortezomib; D017931:DNA Primers; D004317:Doxorubicin; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D016315:Proto-Oncogene Proteins c-abl; D011719:Pyrazines; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases