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

Abstract

BMI1 is a key component of the PRC1 complex (polycomb repressive complex-1) 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.

The anti‐mitotic agents PTC‐028 and PTC596 display potent activity in pre‐clinical models of multiple myeloma but challenge the role of BMI‐1 as an essential tumour gene

“…4 BMI-1 was also shown to play a central role in cancer stem cell growth and survival in various neoplasia. [4][5][6][7] Mechanistically, BMI-1 acts as part of the polycomb repressive complex 1 (PRC1), which represses gene expression via mono-ubiquitination of histone H2A at lysine 119. This process is tightly coupled with PRC2-mediated histone H3 lysine 27 (H3K27)-trimethylation and initiates the recruitment of DNA methyltransferases (DNMTs) for stable silencing of distinct chromatin regions.…”

“…cell cycle, DNA damage, apoptosis, senescence, and self‐renewal of stem cells) 4 . BMI‐1 was also shown to play a central role in cancer stem cell growth and survival in various neoplasia 4‐7 . Mechanistically, BMI‐1 acts as part of the polycomb repressive complex 1 (PRC1), which represses gene expression via mono‐ubiquitination of histone H2A at lysine 119.…”

Deregulation of the pRb-E2F4 axis alters epidermal homeostasis and favors tumor development

“…As the conventional role of pRb/E2F4 in cell cycle regulation is to act repressing gene expression, such increased expression in repressor E2Fs, together with the observed involvement of various Polycomb members in the repressed genes, would provide a possible explanation of how the absence of this classical repressor complex (Rb-E2F4) can induce gene repression. Also in this regard, a functional interaction between repressor E2F and polycomb members mediating gene repression has been previously reported [ 50 , 51 ].…”

Upregulation of ECT2 is associated with transcriptional program of cancer stem cells and predicts poor clinical outcome in gastric cancer

“…4A ). Notably, BUB1 mitotic checkpoint serine/threonine kinase and E2F7, two genes previously reported to account for CSC functionality ( 20 – 22 ), were strongly enriched in ECT2 High gastric cancer samples ( Fig. 4B ).…”

“…BUB1 and E2F7 upregulation have previously been demonstrated to play important roles in essential cellular processes, such as cell proliferation ( 25 – 27 ). It is speculated that BUB1 and E2F7 may be associated with transcriptional features of CSCs ( 20 – 22 ). A previous study revealed that BUB1 depletion using shRNAs reduces cancer stem cell potential of the MDA-MB-231 breast cancer cell line, resulting in inhibited formation of xenografts in immunocompromised mice ( 20 ).…”