Disease relevance of Bmi1

• Complementation with CITED2-expressing retrovirus enhanced proliferation, induced Bmi1/Mel18 expression, and decreased INK4a/ARF expression [1].
• We have used provirus tagging in the Emu Bmi1 mice to identify genes that cooperate with Bmi1 in lymphomagenesis [2].
• Bmi1(-/-) mice also presented more astrocytes at birth, and a generalized gliosis at postnatal day 30 [3].
• Experimental model systems have demonstrated that enhanced expression of individual PcG genes, such as Bmi1, results in the development of B-cell and T-cell lymphomas [4].
• Consistent with a role of Bmi1 in neuroblastoma tumorigenesis we found strong Bmi1 expression in primary neuroblastomas [5].
• Because Bmi1 affects not only mammary stem cells but also more committed cells, our data warrant a more detailed analysis of the different roles of Bmi1 in breast-cancer etiology [6].

High impact information on Bmi1

• To identify new immortalizing genes with potential roles in tumorigenesis, we performed a genetic screen aimed to bypass the rapid and tight senescence arrest of primary fibroblasts deficient for the oncogene Bmi1 [7].
• Most importantly, we provide evidence that the proliferative potential of leukaemic stem and progenitor cells lacking Bmi-1 is compromised because they eventually undergo proliferation arrest and show signs of differentiation and apoptosis, leading to transplant failure of the leukaemia [8].
• A gene expression analysis revealed that the expression of stem cell associated genes, cell survival genes, transcription factors, and genes modulating proliferation including p16Ink4a and p19Arf was altered in bone marrow cells of the Bmi-1-/- mice [9].
• Transplanted fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to contribute only transiently to haematopoiesis [9].
• We found that adult and fetal mouse and adult human HSCs express the proto-oncogene Bmi-1 [9].

Biological context of Bmi1

• Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation [10].
• We show that Arf is a general target of Bmi1, however particularly in neural stem cells, derepression of Ink4a contributes to Bmi1(-/-) phenotypes [11].
• The murine Polycomb-Group (PcG) proteins Eed and Bmi1 govern axial patterning during embryonic development by segment-specific repression of Hox gene expression [10].
• The BM microenvironment in Bmi1(-/-) mice appeared severely defective in supporting hematopoiesis [12].
• Polycomb group proteins Ring1b and Bmi1 (B-cell-specific Moloney murine leukaemia virus integration site 1) are critical components of the chromatin modulating PRC1 complex [13].

Anatomical context of Bmi1

• Beyond axial patterning, Bmi1 is also involved in hemopoiesis because a loss-of-function allele causes a profound decrease in bone marrow progenitor cells [10].
• However, the genetic interaction between the two genes is cell-type specific as the presence of one or two mutant alleles of eed trans-complements the Bmi1-deficiency in pre-B bone marrow cells [10].
• We used a genetic approach to investigate whether Ink4a or Arf is more critical for relaying Bmi1 function in lymphoid cells, neural progenitors, and neural stem cells [11].
• Transcriptional coactivator Cited2 induces Bmi1 and Mel18 and controls fibroblast proliferation via Ink4a/ARF [1].
• BMI1 loss delays photoreceptor degeneration in Rd1 mice. Bmi1 loss and neuroprotection in Rd1 mice [14].

Associations of Bmi1 with chemical compounds

• At both stages, colocalization of bromodeoxyuridine and GFAP demonstrated that Bmi1 loss did not prevent astrocyte precursor proliferation [3].
• A plasmid expressing antisense Bmi-1 mRNA was then constructed by reverse design of PCR primers and cloned to the plasmid pLNCX2; G418 was added to the medium after the plasmid was successfully introduced in K562 cells by lipofectin-mediated DNA transfection [15].

Physical interactions of Bmi1

• Co-immunoprecipitations and subnuclear co-localization studies show that MPc2 interacts with the mouse polycomb-group oncoprotein Bmi1 and is a new member of the mouse polycomb multiprotein complex [16].
• The Bmi-1 oncoprotein interacts with dinG and MPh2: the role of RING finger domains [17].

Regulatory relationships of Bmi1

• The Polycomb group (PcG) gene Bmi1 promotes cell proliferation and stem cell self-renewal by repressing the Ink4a/Arf locus [11].

Other interactions of Bmi1

• We found that Cited2(-/-) fibroblasts had reduced expression of the polycomb-group genes Bmi1 and Mel18, which function as INK4a/ARF and Hox repressors [1].
• This has yielded a series of oncogenes that could be assigned to different complementation groups in transformation: the myc, Pim, Bmi1, and Frat1 complementation groups [18].
• Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice [11].
• These studies thus suggest that hemopoietic cell proliferation is regulated by the relative contribution of repressive (Eed-containing) and enhancing (Bmi1-containing) PcG gene complexes [10].
• Here we demonstrate that down-regulation of ink4a-ARF by Bmi-1 underlies its ability to cooperate with Myc in tumorigenesis [19].

Analytical, diagnostic and therapeutic context of Bmi1

• Bmi1, a polycomb group protein, is also down-regulated immediately after treatment and remains at a low level during the induction [20].
• Chromatin immunoprecipitation (ChIP) assays demonstrate that Bmi-1 and other components of the two PcG complexes bind to the promoter of HoxC13 [21].
• We have used both in vitro cultivation and a xenograft mouse model to examine the role of hedgehog signaling and Bmi-1 in regulating self-renewal of normal and malignant human mammary stem cells [22].
• EXPERIMENTAL DESIGN: We measure the expression of PcG members Bmi-1, Mel-18, and Hpc-2 and their potential targets by reverse transcription-PCR, immunostaining, and Western blotting in a series of 134 breast carcinomas and correlate the data with several clinical-pathologic variables of the tumors [23].
• We have analysed the expression patterns of several Hox genes by RNA in situ hybridization on serial sections of 11.5- and 12.5-day Bmi-1 null mutant embryos [24].

References