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Acute lymphoblastic leukemia

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

Leukemia volume 30, pages 1682–1690 (2016)Cite this article

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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.

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Acknowledgements

This work was supported, in part, by the NCI grant RO1 CA167169 (to BC) and by the SKCC support grant P30 CA056036. Dr Samanta A Mariani was supported, in part, by an AIRC-Marie Curie international fellowship.

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Authors and Affiliations

  1. Department of Cancer Biology and Sydney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    S A Mariani, V Minieri, M De Dominici & B Calabretta

  2. Department of Hematology, University of Bologna, Bologna, Italy

    I Iacobucci

  3. Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI, USA

    L F Peterson

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  1. S A Mariani
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Correspondence to B Calabretta.

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Mariani, S., Minieri, V., De Dominici, M. et al. CDKN2A-independent role of BMI1 in promoting growth and survival of Ph+ acute lymphoblastic leukemia. Leukemia 30, 1682–1690 (2016). https://doi.org/10.1038/leu.2016.70

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