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Aneuploidy-inducing gene knockdowns overlap with cancer mutations and identify Orp3 as a B-cell lymphoma suppressor

Oncogene volume 39, pages 1445–1465 (2020)Cite this article

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Abstract

Aneuploidy can instigate tumorigenesis. However, mutations in genes that control chromosome segregation are rare in human tumors as these mutations reduce cell fitness. Screening experiments indicate that the knockdown of multiple classes of genes that are not directly involved in chromosome segregation can lead to aneuploidy induction. The possible contribution of these genes to cancer formation remains yet to be defined. Here we identified gene knockdowns that lead to an increase in aneuploidy in checkpoint-deficient human cancer cells. Computational analysis revealed that the identified genes overlap with recurrent mutations in human cancers. The knockdown of the three strongest selected candidate genes (ORP3, GJB3, and RXFP1) enhances the malignant transformation of human fibroblasts in culture. Furthermore, the knockout of Orp3 results in an aberrant expansion of lymphoid progenitor cells and a high penetrance formation of chromosomal instable, pauci-clonal B-cell lymphoma in aging mice. At pre-tumorous stages, lymphoid cells from the animals exhibit deregulated phospholipid metabolism and an aberrant induction of proliferation regulating pathways associating with increased aneuploidy in hematopoietic progenitor cells. Together, these results support the concept that aneuploidy-inducing gene deficiencies contribute to cellular transformation and carcinogenesis involving the deregulation of various molecular processes such as lipid metabolism, proliferation, and cell survival.

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Acknowledgements

This work was supported by the Erich und Gertrud Roggenbuck Stiftung and Deutsche Krebshilfe (C. Günes, grant 10–2086-Gü 2), the European Union (advanced ERC grant to K. L. Rudolph, grant 323136), and the German Science Foundation (DFG, grants: SFB 1074 Projekt Z1 and GRK 2254 HEIST to H.A. Kestler). A.K. was supported by a Strategy and Innovation Grant from the Free State of Thuringia (41–5507–2016) and the Leibniz ScienceCampus InfectoOptics (SAS-2015-HKI-LWC). The FLI Core Facilities; Flow Cytometry, Histology, S2 laboratory, and Mouse facilities are gratefully acknowledged. We would like to thank the members of the K.L. Rudolph laboratory for helpful support. We thank Lars Zender and Torsten Wüstefeld for the cooperation in providing the lentiviral shRNA library targeting human cells and deep sequencing expertize. We also thank Sabrina Eichwald and Michaela Eggel for technical support and Lucien Frappart for his help with the histological evaluation of the xenograft mouse tumors. We acknowledge the Leibniz Graduate School on Ageing and Age-Related Diseases (LGSA), the government of Kenya and the Federal Government of Germany for financing S.N.N. through DAAD/NACOSTI (present NRF) scholarship

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Author notes

  1. Sospeter N. Njeru

    Present address: Paul-Ehrlich-Institute, Division Immunology, 63225, Langen, Germany

  2. Jitendra K. Meena

    Present address: Baylor College of Medicine, Houston, TX, USA

  3. Andreas Koeberle

    Present address: Michael Popp Research Institute, University of Innsbruck, Innsbruck, Austria

  4. These authors contributed equally: Sospeter N. Njeru, Johann Kraus, Jitendra K. Meena

  5. These authors jointly supervised this work: Hans A. Kestler, Cagatay Günes, K. Lenhard Rudolph

Authors and Affiliations

  1. Leibniz Institute on Aging, Fritz Lipmann Institute e.V., 07745, Jena, Germany

    Sospeter N. Njeru, Jitendra K. Meena, Omid Omrani, Christian Hoischen & K. Lenhard Rudolph

  2. Institute of Medical Systems Biology, Ulm University, 89081, Ulm, Germany

    Johann Kraus & Hans A. Kestler

  3. Department of Internal Medicine I, Ulm University Hospital, 89081, Ulm, Germany

    André Lechel & Sarah-Fee Katz

  4. Department of Urology, Ulm University Hospital, 89081, Ulm, Germany

    Mukesh Kumar, Anca Azoitei, Felix Wezel, Christian Bolenz & Cagatay Günes

  5. Department of General and Visceral Surgery, Ulm University Hospital, 89081, Ulm, Germany

    Uwe Knippschild

  6. Institute of Pathology, Ulm University, 89075, Ulm, Germany

    Frank Leithäuser

  7. Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743, Jena, Germany

    André Gollowitzer & Andreas Koeberle

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  1. Sospeter N. Njeru
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Contributions

Conception and design (CG, HAK, and KLR); Acquisition of data (CG, SNN, JKM, MK, AL, SFK, AG, AA, OO, CH); Analysis and interpretation of data (CG, KLR, HAK, SNN, JK, JKM, UK, AK, AG, FL, FW, CB); Writing of the manuscript (SNN, CG, HAK, and KLR). All the authors read and approved the final manuscript.

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Correspondence to Hans A. Kestler, Cagatay Günes or K. Lenhard Rudolph.

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Njeru, S.N., Kraus, J., Meena, J.K. et al. Aneuploidy-inducing gene knockdowns overlap with cancer mutations and identify Orp3 as a B-cell lymphoma suppressor. Oncogene 39, 1445–1465 (2020). https://doi.org/10.1038/s41388-019-1073-2

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