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Inactivating CUX1 mutations promote tumorigenesis

Nature Genetics volume 46, pages 33–38 (2014)Cite this article

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Abstract

A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ∼1–5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.

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Figure 1: Identification and significance of CUX1 mutations in human cancer.
Figure 2: Identification of CUX1 as a tumor suppressor gene in mice and Drosophila.
Figure 3: CUX1 deficiency activates PI3K signaling associated with downregulation of the PI3K inhibitor, PIK3IP1.
Figure 4: CUX1 directly regulates PIK3IP1 expression and CUX1 deficiency increases sensitivity to PI3K-AKT-mTOR inhibition.

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Acknowledgements

The PLKO.pig vector was a kind gift from I. Lemischka (Mount Sinai School of Medicine). Plasmids pXJ42 and pXJ myc-CUX1p110-HA were kindly provided by A. Nepveu (McGill University). We thank D. Pask, J. Carter, T. Hamilton and staff of the Sanger RSF for animal husbandry. C.C.W. and D.J.A. are supported by Cancer Research UK, The Wellcome Trust and the European Research Council. S.J.B. and S.L. are supported by the Medical Research Council. Work in the A.R.G. laboratory is supported by Leukemia and Lymphoma Research, Cancer Research UK, the Kay Kendall Leukaemia Fund, the NIHR Cambridge Biomedical Research Centre, the Cambridge Experimental Cancer Medicine Centre, and the Leukemia & Lymphoma Society of America. I.M. is supported by an EMBO Long-Term Fellowship. J.N. is supported by a Kay Kendall Leukaemia Fund Clinical Fellowship. U.M. is supported by a Cancer Research UK Clinician Scientist Fellowship.

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  1. Christina Kober

    Present address: Present address: Department of Biochemistry, Biocenter University of Würzberg, Würzberg, Germany.,

Authors and Affiliations

  1. Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Chi C Wong, Alistair G Rust, Mamunur Rashid, Jessamy C Tiffen, Christina Kober & David J Adams

  2. Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK

    Chi C Wong, Anthony R Green, Charles E Massie, Jyoti Nangalia & Peter J Campbell

  3. The Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Inigo Martincorena, Constantine Alifrangis, Ludmil B Alexandrov, Ultan McDermott, Elli Papaemmanuil & Peter J Campbell

  4. Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, UK

    Anthony R Green, Charles E Massie & Jyoti Nangalia

  5. Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK

    Anthony R Green, Charles E Massie & Jyoti Nangalia

  6. Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK

    Stella Lempidaki & Sarah J Bray

  7. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    Hartmut Döhner & Konstanze Döhner

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Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium

Contributions

C.C.W. and D.J.A. conceived the study and wrote the paper. A.G.R., I.M., L.B.A., P.J.C., M.R., E.P., C.K., U.M., C.A., J.C.T., A.R.G., C.E.M., J.N., S.L., S.J.B., H.D. and K.D. performed experiments and analysis. The Chronic Myeloid Disorders Working Group supervised the MDS and MDS/MPN exome study.

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Correspondence to David J Adams.

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Wong, C., Martincorena, I., Rust, A. et al. Inactivating CUX1 mutations promote tumorigenesis. Nat Genet 46, 33–38 (2014). https://doi.org/10.1038/ng.2846

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