Original Article

Leukemia (2016) 30, 1682–1690; doi:10.1038/leu.2016.70; published online 29 April 2016

Acute lymphoblastic leukemia

CDKN2A-independent role of BMI1 in promoting growth and survival of Ph+ acute lymphoblastic leukemia

S A Mariani1, V Minieri1, M De Dominici1, I Iacobucci2, L F Peterson3 and B Calabretta1

  1. 1Department of Cancer Biology and Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
  2. 2Department of Hematology, University of Bologna, Bologna, Italy
  3. 3Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA

Correspondence: Professor B Calabretta, Department of Cancer Biology and Sydney Kimmel Cancer Center, Thomas Jefferson University, 233 S 10th Street, Philadelphia, PA 19107, USA. E-mail: Bruno.calabretta@jefferson.edu

Received 23 June 2015; Revised 3 March 2016; Accepted 15 March 2016
Accepted article preview online 5 April 2016; Advance online publication 29 April 2016

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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.