Disease relevance of BMI1

• They also colocalize with BMI1 in interphase nuclei of U-2 OS human osteosarcoma and SW480 human colorectal adenocarcinoma cells [1].
• CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes [2].
• We also demonstrate linked overexpression of BMI1 and patched (PTCH), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas [3].
• Changes in expression associated with tumoral transformation have been found for BMI1 and RNF2, which exhibited increased expression in a large series of tumors, including gastrointestinal tumors, pituitary and parathyroid adenomas, and lymphomas, compared with their expression in normal-cell counterparts [4].
• The high level of expression of BMI1 protein observed in mantle-cell lymphomas and pituitary adenomas is associated in some cases with amplification of BMI1 locus [4].
• In a cohort of 64 CML patients, the level of BMI1 at diagnosis correlated with time to transformation to blast crisis, and the combination of low BMI1 and high proteinase-3 expression was associated in multivariate analysis with an improved overall survival (P = .001) [5].

High impact information on BMI1

• The HPC/HPH PcG complex contains the human polycomb 2 (HPC2; ref. 11), human polyhomeotic (HPH), BMI1 (ref. 13 ) and RING1 (refs 14, 15) proteins [6].
• Here, we demonstrate that Polycomb genes EZH2 and BMI1 repress p16 expression in human and mouse primary cells, but not in cells deficient for pRB protein function [7].
• Genetic studies have demonstrated that Bmi1 promotes cell proliferation and stem cell self-renewal with a correlative decrease of p16(INK4a) expression [7].
• Together, these findings identify E4F1 as a key modulator of BMI1 activity in primitive hematopoietic cells [8].
• E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells [8].

Biological context of BMI1

• Chromatin-association of the Polycomb group protein BMI1 is cell cycle-regulated and correlates with its phosphorylation status [9].
• In primary and tumor cells, nuclear BMI1 shows a fine-grain distribution over chromatin, usually dense in interphase nuclei and significantly weaker along mitotic chromosomes [9].
• BMI1 controls cellular proliferation through suppression of the tumor suppressors encoded by the CDKN2A locus [2].
• BMI1 gene expression was significantly down-regulated with increasing donor age, whereas no striking age differences were observed for Ki67 [10].
• Despite a significant overlap in dosage-sensitive homeotic phenotypes and co-repression of a similar set of Hox genes, genetic analysis implicated eed and Bmi1 in parallel pathways, which converge at the level of Hox gene regulation [11].

Anatomical context of BMI1

• HPH1, HPH2, and BMI1 show distinct, although overlapping expression patterns in different tissues and cell lines [1].
• In addition, BMI1 preferentially associates with several distinct heterochromatic domains in tumor cell lines [9].
• The analysis revealed increased expression of a set of PcG proteins (particularly RYBP and BMI1) in tumour cells in comparison with reactive lymphoid tissue [12].
• Dysregulated expression of stem cell factor bmi1 in precancerous lesions of the gastrointestinal tract [13].
• Moderate to high BMI-1 expression was detected in AML patients, and the BMI-1 expression levels in AML samples were significantly higher than in normal bone marrow controls (P = .0011) [14].

Associations of BMI1 with chemical compounds

• We also demonstrated that loss of BMI1 was more effective in suppressing cancer cell growth than retinoid-treatment, and surviving cancer cells showed significantly reduced tumorigenicity [15].

Physical interactions of BMI1

• HPH1 and HPH2 coimmunoprecipitate and cofractionate with each other and with BMI1 [1].
• Here we report the identification of E4F1, an inhibitor of cellular proliferation, as a novel BMI1-interacting partner in hematopoietic cells [8].
• Loss of Dmap1 binding to the Bmi1 target loci was tightly associated with derepressed gene expression in Bmi1(-/-) cells [16].

Enzymatic interactions of BMI1

• Here, we report that the E3 ubiquitin ligase consisting of SPOP and CULLIN3 is able to ubiquitinate the Polycomb group protein BMI1 and the variant histone MACROH2A [17].

Regulatory relationships of BMI1

• In immunofluorescence co-expression studies, Ki67-positive cells were negative for p16(INK4A) and BMI1-expressing cells also stained negatively for Ki67 [10].

Other interactions of BMI1

• Association of BMI1 with polycomb bodies is dynamic and requires PRC2/EZH2 and the maintenance DNA methyltransferase DNMT1 [18].
• Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers [13].
• Here, we investigate the kinetic properties of the binding of one of the PRC1 core components, BMI1, with PcG bodies [18].
• In both primary and tumor cell lines a marked cell cycle-regulation of Pc-G-chromatin interaction is observed: nuclear BMI1-staining dissipates in late S phase and is re-established early in G(1)-phase [9].
• The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex [19].

Analytical, diagnostic and therapeutic context of BMI1

• To determine whether p16(INK4A) expression in human skin correlates with donor age, p16(INK4A) expression was analyzed by immunohistochemistry as well as the expression of the p16(INK4A) repressor BMI1 [10].
• The expression of hTRAP and BMI-1 were detected by real-time PCR and Western blotting [20].
• Fluorescence in situ hybridization (FISH) on metaphase chromosome spreads located the human BMI-1 gene to the short arm of chromosome 10 (10p13), a region known to be involved in translocations in various leukemias [21].
• BMI-1 and p16INK4a mRNA and protein expression were also studied by real-time quantitative reverse transcription-PCR and Western blot, respectively, in a subset of NHLs [22].
• To determine the possible alterations of this gene in human malignancies, we have examined 160 lymphoproliferative disorders, 13 myeloid leukemias, and 89 carcinomas by Southern blot analysis and detected BMI-1 gene amplification (3- to 7-fold) in 4 of 36 (11%) mantle cell lymphomas (MCLs) with no alterations in the INK4a/ARF locus [22].

References