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

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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.

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Figure 1: MM cells present ongoing DNA damage, driving ABL1 inside the nucleus.
Figure 2: pATM and pJNK modulate ABL1 nuclear relocalization.
Figure 3: YAP1 deletions and expression in MM cell lines and samples from subjects with MM.
Figure 4: YAP1 re-expression leads to ABL1-dependent proliferation reduction and cell death.
Figure 5: STK4 knockdown triggers YAP1 re-expression, reducing MM cell proliferation and increasing apoptosis in vitro and in vivo.
Figure 6: Lymphoma, leukemia and Waldenström macroglobulinemia cells present ongoing DNA damage and ABL1 nuclear localization and undergo apoptosis after STK4-mediated increases in YAP1 levels.

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Acknowledgements

We thank M. Sudol (Mount Sinai School of Medicine) for the eGFP-YAP1 construct, W. Hahn (Dana-Farber Cancer Institute) for pLKO.1 shRNA lentiviral vectors and S. Rosen (Northwestern University) and R. Burger (University of Kiel) for MM.1R and INA-6 MM cells. We also thank E. Di Cairano and L. Spagnuolo for immunohistochemical stains, F. Ghini and A.M. Gasparri for technical help, the Dana-Farber Cancer Institute Flow cytometry facility, D. Kufe and F. Bernassola for insightful suggestions, C. Brennan for the bioinformatics analysis and members of the Anderson and Tonon lab for sharing reagents and critical reading of the manuscript. W.M.K. is supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. This work was supported by Fondazione CARIPLO, a Marie Curie International Reintegration Grant and the Associazione Italiana per la Ricerca sul Cancro (AIRC; AIRC Special Program Molecular Clinical Oncology, 5 per mille no. 9980 to A.N. and Investigator Grants and Special Program Molecular Clinical Oncology, 5 per mille no. 9965 to G.T.) (G.T.). K.C.A. is an American Cancer Society Clinical Research Professor and is supported by NIH grants NIH SPORE P50 100707, PO-1 78378 and RO-1 50947.

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F.C. designed research, performed experiments, analyzed data and wrote the manuscript. T.H. designed research and analyzed data. C.X., E.t.H., E.A. and M.T.B. performed mouse experiments. M.S., A.C.K., K.-K.W., G.B. and F.C.-C. contributed to designing experiments. M.D., L.A. and A.N. analyzed genomic and microarray data. M.P. and R.C. analyzed immunohistochemistry staining. M.M. and P.G.R. provided patient samples. W.M.K. analyzed data and wrote the manuscript. K.C.A. analyzed data and wrote the manuscript. G.T. designed research, analyzed data and wrote the manuscript.

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Correspondence to Kenneth C Anderson or Giovanni Tonon.

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Cottini, F., Hideshima, T., Xu, C. et al. Rescue of Hippo coactivator YAP1 triggers DNA damage–induced apoptosis in hematological cancers. Nat Med 20, 599–606 (2014). https://doi.org/10.1038/nm.3562

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