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.
Subject(s)
Polycomb Repressive Complex 1/physiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Animals , Apoptosis , Cell Line , Cell Proliferation , Cell Survival , Cyclin-Dependent Kinase Inhibitor p16 , Gene Expression Regulation , Gene Transfer Techniques , Humans , Interferon-alpha/pharmacokinetics , Mice , Polycomb Repressive Complex 1/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolismABSTRACT
Lip carcinoma is a relatively unique malignant disease because the lip is a junctional structure. The lip is bounded externally by the facial skin and it is in continuity with the buccal mucosa of the oral cavity. The lymphatic drainage of the upper and lower lips is primarily directed to the mandibular group of lymph nodes. To a lesser extent, drainage may go to submental intraparotid, or internal jugular lymph nodes. Lip carcinoma is almost exclusively a squamous cell carcinoma, the major etiologic factor being prolonged iar exposure. Treatment for lip carcinoma is usually surgical, in the form of full-tickness excision. Neck dissection is also performed when clinically palpable lymph nodes are present.
