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Chronic myelogenous leukemia

The BMI1 polycomb protein represses cyclin G2-induced autophagy to support proliferation in chronic myeloid leukemia cells

Leukemia volume 29, pages 1993–2002 (2015)Cite this article

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Abstract

The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCζ-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response.

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Acknowledgements

We are grateful to Malek Djabali (UMR5088 CNRS, Toulouse, France) for helpful discussion during early phases of the project; Hans Clevers (Hubrecht Laboratory, Utrecht, The Netherlands) for the kind gift of the pTER vector; Agnès Loubat for help in cell cycle analysis; Jan Jacob Schuringa (University Medical Center Groningen, Hematology, Groningen, The Netherlands) for the kind gift of the shBMI1 lentiviral constructs; Patrick Auberger, Arnaud Jacquel and Sandrine Obba for helpful discussion concerning autophagy; Catherine Frelin for critical review of the manuscript. We thank Ms Chimène Morillon and Kevin Lebrigand from the Plateforme Génomique Fonctionnelle (IPMC, Sophia Antipolis, France) for Affymetrix analysis assistance and Dr Bernard Mari for help with transcriptomic analyses. We acknowledge the C3M imaging core facility (Microscopy and Imaging Platform Côte d'Azur) and the C3M animal room facility. The C3M is supported institutional grants from INSERM. LM is supported by a grant from the French Ministry of Research and a 4th year PhD grant from the Société Française d’Hématologie (SFH).

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Gene profiling was performed on inducible shBmi1-K562 cells incubated or not with doxycycline (1μg/ml) for 96h using HG-U133 Plus2 Affymetrix Arrays.

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Author notes

  1. D Mary and J-F Peyron: These authors share senior coauthorship.

Authors and Affiliations

  1. INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France

    L Mourgues, V Imbert, M Nebout, P Colosetti, Z Neffati, P Lagadec, E Verhoeyen, D Mary & J-F Peyron

  2. Equipe Inflammation, Cancer, Cancer Stem Cells, Nice, France

    L Mourgues, V Imbert, M Nebout, Z Neffati, P Lagadec, D Mary & J-F Peyron

  3. Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France

    L Mourgues, V Imbert, M Nebout, P Colosetti, Z Neffati, P Lagadec, L Legros, N Rochet, D Mary & J-F Peyron

  4. Equipe Cell Death, Differentiation and Cancer, Nice, France

    P Colosetti & E Verhoeyen

  5. Equipe Metabolic control of Cell Death in Cancer, Nice, France

    E Verhoeyen

  6. Department of Biology, York University, Toronto, ON, Canada

    C Peng

  7. CRCM, U1068, INSERM, Marseille, France

    E Duprez

  8. Service d'Hématologie Clinique, Hôpital Archet 1, Nice, France

    L Legros

  9. Institut de Biologie Valrose (iBV), UMR CNRS 7277-UMR INSERM 1091, Nice, France

    L Legros & N Rochet

  10. CNRS, UMR5386, INSERM, U1052, Lyon, France

    V Maguer-Satta

  11. Service d’Hématologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite, France

    F-E Nicolini

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  1. L Mourgues
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Mourgues, L., Imbert, V., Nebout, M. et al. The BMI1 polycomb protein represses cyclin G2-induced autophagy to support proliferation in chronic myeloid leukemia cells. Leukemia 29, 1993–2002 (2015). https://doi.org/10.1038/leu.2015.112

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