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Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1

Leukemia volume 31, pages 1625–1629 (2017)Cite this article

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Chronic lymphocytic leukemia (CLL), the most common adulthood leukemia, is characterized by an accumulation of abnormal CD5+ B lymphocytes in the peripheral blood, bone marrow and secondary lymphoid organs. Acquired genetic mutations play an important role in CLL pathogenesis, and massive parallel sequencing identified new recurrently mutated genes such as NOTCH1, S3FB1, XPO1, MYD88, EGR2 and NFKBIE.1, 2, 3, 4 In addition, frequent chromosomal abnormalities, such as 11q, 13q and 17p deletions, or trisomy 12 could explain both the clinical heterogeneity of CLL and the drug resistance of this disease.5 Therefore, identifying deregulated genes in CLL are important to improving our understanding about the development and evolution of CLL, and to propose new targeted strategies.

We and others have previously reported that the gain of the short arm of chromosome 2 (2p+) is a frequent chromosomal abnormality in CLL. MYCN, REL, BCL11A and MSH2 have been proposed as candidate disease genes associated with a 2p gain, although the underlying mechanisms have not been elucidated.6, 7, 8, 9, 10, 11 In this study, we identified chromosome region maintenance/exportin-1 (CRM1/XPO1) as a critical gene in CLL patients by unveiling a minimal 2p gained region. Thus we assessed the response of 2p+/CLL cells to commonly used anti-CLL drugs, including the tri-therapy fludarabine, cyclophosphamide, rituximab (FCR), ibrutinib, rituximab-idelalisib (R-Idelalisib) and the XPO1 inhibitor selinexor.12

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Acknowledgements

We thank the Centre de Ressource Biologique de Caen for Lepretre’s trial samples. We are also grateful to O Bernard for critical comments, X Troussard, R Guieze, S Struski, E Fonteneau, R Delepine, O Kosmider, D Bouscary, C Delacroix and L Cabon for invaluable help, and LY Sebaert for the gift of the JVM-3 cell line. OSU-CLL cells were provided by The Ohio State University’s Human Genetics Sample Bank. This work was supported by Roche Diagnostics, the Association Laurette Fugain (ALF10/09, ALF14/08 and ALF 15/09), Ligue Contre le Cancer (RS15/75-63 and RS16/75-50) and Fondation ARC (Association pour la Recherche sur le Cancer) (SFI20111203530 and PJA20151203407). AC holds PhD fellowships from Fondation pour la Recherche Medicale (FDT20140931078) and Société Française d’Hématologie.

Author contributions

AC conceived and performed experimental work, analyzed the data, and helped to write the manuscript. EC, NB, H-AC, CA, CG, LH and M-NB-N conceived, and performed experimental work and analyzed the data. FD, HM-B, SC, MU, VM, VL, KM, SL, PF, LS, MLG-T enrolled patients and managed CLL samples. JL, CL, JLe performed statistical analysis. YL provided selinexor and KPT-301. SAS and FN-K conceived and supervised the project, designed experiments, interpreted the data and wrote the manuscript.

Author information

Author notes

  1. E Chapiro and N Bougacha: These authors contributed equally to this work.

  2. S A Susin and F Nguyen-Khac: Senior coauthorship.

Authors and Affiliations

  1. INSERM UMR_S 1138, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, Centre de Recherche des Cordeliers, Paris, France

    A Cosson, E Chapiro, N Bougacha, L Herbi, M-N Brunelle-Navas, F Davi, H Merle-Béral, M Le Garff-Tavernier, S A Susin & F Nguyen-Khac

  2. Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France

    A Cosson, E Chapiro, N Bougacha, L Herbi, M-N Brunelle-Navas, F Davi, H Merle-Béral, M Le Garff-Tavernier, S A Susin & F Nguyen-Khac

  3. Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France

    A Cosson, N Bougacha, L Herbi, M-N Brunelle-Navas & S A Susin

  4. Service d’Hématologie Biologique, GH Pitié-Salpêtrière, Paris, France

    E Chapiro, H-A Cung, C Algrin, C Gabillaud, F Davi, H Merle-Béral, M Le Garff-Tavernier, S Choquet, M Uzunov, V Morel, V Leblond, K Maloum, C Lesty & F Nguyen-Khac

  5. Service de Biostatistique et Informatique Médicale, Hôpital Saint Louis, Paris, France

    J Lambert & J Lejeune

  6. Département de génétique, GH Pitié-Salpêtrière, Paris, France

    B Keren

  7. INSERM U1170, Institut Gustave Roussy, Villejuif, France

    F Damm & D Roos-Weil

  8. Département d’Hématologie, Hôpital Becquerel, Rouen, France

    S Lepretre

  9. Pôle d’Hématologie, Hôpital Brabois, Vandoeuvre-les-Nancy, France

    P Feugier

  10. Service d’Hématologie Clinique, Hôpital d’Argenteuil, Argenteuil, France

    L Sutton

  11. Karyopharm Therapeutics, Newton, MA, USA

    Y Landesman

Authors
  1. A Cosson
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  2. E Chapiro
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  19. V Leblond
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  20. K Maloum
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  21. S Lepretre
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  27. S A Susin
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  28. F Nguyen-Khac
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Corresponding authors

Correspondence to S A Susin or F Nguyen-Khac.

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Competing interests

YL is an employee of Karyopharm Therapeutics Inc. and receives compensation, and holds equity in the company. The remaining authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Cosson, A., Chapiro, E., Bougacha, N. et al. Gain in the short arm of chromosome 2 (2p+) induces gene overexpression and drug resistance in chronic lymphocytic leukemia: analysis of the central role of XPO1. Leukemia 31, 1625–1629 (2017). https://doi.org/10.1038/leu.2017.100

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