title: CDKN2A-independent role of BMI1 in promoting growth and survival of Ph+ acute lymphoblastic leukemia.
abstract: BMI1 is a key component of the PRC1 (polycomb repressive complex-1) complex required for maintenance of normal and cancer stem cells. Its aberrant expression is detected in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL), but no data exist on BMI1 requirement in ALL cells. We show here that BMI1 expression is important for proliferation and survival of Ph+ ALL cells and for leukemogenesis of Ph+ cells in vivo. Levels of BIM, interferon-α (IFNα)-regulated genes and E2F7 were upregulated in BMI1-silenced cells, suggesting that repressing their expression is important for BMI1 biological effects. Consistent with this hypothesis, we found that: (i) downregulation of BIM or E2F7 abrogated apoptosis or rescued, in part, the reduced proliferation and colony formation of BMI1 silenced BV173 cells; (ii) BIM/E2F7 double silencing further enhanced colony formation and in vivo leukemogenesis of BMI1-silenced cells; (iii) overexpression of BIM and E2F7 mimicked the effect of BMI1 silencing in BV173 and SUP-B15 cells; and (iv) treatment with IFNα suppressed proliferation and colony formation of Ph+ ALL cells. These studies indicate that the growth-promoting effects of BMI1 in Ph+ ALL cells depend on suppression of multiple pathways and support the use of IFNα in the therapy of Ph+ ALL.
authors.affiliation: Department of Cancer Biology and Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Mariani
authors.affiliation: Department of Cancer Biology and Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Minieri
authors.affiliation: Department of Cancer Biology and Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: De Dominici
authors.affiliation: Department of Hematology, University of Bologna, Bologna, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Iacobucci
authors.affiliation: Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Peterson
authors.affiliation: Department of Cancer Biology and Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Calabretta
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006801:Humans; D016898:Interferon-alpha / Q000493:pharmacokinetics; D051379:Mice; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000502:physiology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*
chemical_list: C069077:BMI1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016898:Interferon-alpha; D063150:Polycomb Repressive Complex 1