The BMI1 polycomb protein represses cyclin G2-induced autophagy to support proliferation in chronic myeloid leukemia cells.
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.
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Equipe Inflammation, Cancer, Cancer Stem Cells, Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.
L
L
Mourgues
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Equipe Inflammation, Cancer, Cancer Stem Cells, Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.
V
V
Imbert
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Equipe Inflammation, Cancer, Cancer Stem Cells, Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.
M
M
Nebout
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.|Equipe Cell Death, Differentiation and Cancer, Nice, France.
P
P
Colosetti
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Equipe Inflammation, Cancer, Cancer Stem Cells, Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.
Z
Z
Neffati
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Equipe Inflammation, Cancer, Cancer Stem Cells, Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.
P
P
Lagadec
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Equipe Cell Death, Differentiation and Cancer, Nice, France.|Equipe Metabolic control of Cell Death in Cancer, Nice, France.
E
E
Verhoeyen
Department of Biology, York University, Toronto, ON, Canada.
C
C
Peng
CRCM, U1068, INSERM, Marseille, France.
E
E
Duprez
Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.|Service d'Hématologie Clinique, Hôpital Archet 1, Nice, France.|Institut de Biologie Valrose (iBV), UMR CNRS 7277-UMR INSERM 1091, Nice, France.
L
L
Legros
Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.|Institut de Biologie Valrose (iBV), UMR CNRS 7277-UMR INSERM 1091, Nice, France.
N
N
Rochet
CNRS, UMR5386, INSERM, U1052, Lyon, France.
V
V
Maguer-Satta
Service d'Hématologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite, France.
F-E
FE
Nicolini
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Equipe Inflammation, Cancer, Cancer Stem Cells, Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.
D
D
Mary
INSERM, UMR1065 Centre Méditerranéen de Médecine Moléculaire C3M, Nice, France.|Equipe Inflammation, Cancer, Cancer Stem Cells, Nice, France.|Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France.
J-F
JF
Peyron
D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D056767:Cyclin G2 / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
C069077:BMI1 protein, human; C101593:CCNG2 protein, human; D056767:Cyclin G2; D034741:RNA, Small Interfering; D063150:Polycomb Repressive Complex 1