Alternative titles; symbols
HGNC Approved Gene Symbol: BMI1
Cytogenetic location: 10p12.2 Genomic coordinates (GRCh38): 10:22,321,099-22,331,484 (from NCBI)
Transgenic mice bearing oncogenes provide valuable new insights into the process of malignant transformation. One of the best studied transgenic mouse models of hematopoietic malignancies is the transgenic mouse overexpressing the c-myc gene in its lymphoid compartment by virtue of the immunoglobulin heavy chain enhancer (E-mu). These mice develop B-cell lymphomas of clonal origin after a variable latency period. Infection of E-mu/myc transgenic mice with Moloney murine leukemia virus (MuLV) is an efficient way to identify oncogenes that synergize with the transgene. In about half of independently induced pre-B-cell lymphomas, the provirus integrates in or near the Bmi1 gene, resulting in enhanced transcription of that gene. The murine Bmi1 protein is found in the nucleus and harbors structural motifs found in nuclear proteins, including a novel putative zinc finger shared by a diverse set of proteins involved in gene regulation, DNA recombination, and DNA repair. The product of the Bmi1 gene showed 70% identity with the Mel18 protein gene (165040), which was isolated from a mouse melanoma cell line. The Bmi1 gene is highly conserved in evolution as indicated by zoo blot hybridization with Bmi1 probes corresponding to the protein-encoding domain. Alkema et al. (1993) isolated the human BMI1 cDNA. The 3,203-bp cDNA shows 86% identity to the mouse nucleotide sequence. The open reading frame encodes a protein of 326 amino acids which shares 98% identity to the 324-amino acid sequence of the mouse protein.
While screening for proteins that interact with the BMI1 protein, Satijn et al. (1997) isolated the RING1 protein (602045). They showed that BMI1 and RING1 bind in vitro and colocalize in the nuclei of 2 types of sarcoma cells. Satijn et al. (1997) stated that BMI1 and RING1 may be part of a protein complex.
According to Lessard and Sauvageau (2003) an emerging concept in the field of cancer biology is that a rare population of 'tumor stem cells' exists among the heterogeneous group of cells that constitute a tumor. This concept, best described with human leukemia, indicates that stem cell function (whether normal or neoplastic) might be defined by a common set of critical genes. Lessard and Sauvageau (2003) showed that BMI1 has a key role in regulating the proliferative activity of normal stem and progenitor cells. Most importantly, they provided evidence that the proliferative potential of leukemic stem and progenitor cells lacking BMI1 is compromised because they eventually undergo proliferation arrest and show signs of differentiation and apoptosis, leading to transplant failure of the leukemia. Complementation studies showed that BMI1 completely rescues these proliferative defects. Lessard and Sauvageau (2003) concluded that BMI1 has an essential role in regulating the proliferative activity of both normal and leukemic stem cells.
Itahana et al. (2003) stated that BMI1 represses the INK4A locus which encodes the tumor suppressors p16(INK4A) and p14(ARF). They found that BMI1 was downregulated during replicative senescence, but not quiescence, in a human fibroblast cell line. Furthermore, overexpression extended the replicative life span of the fibroblasts, and required RB1 (614041) but not p53 (191170). Deletion analysis showed that the RING finger and helix-turn-helix domains of BMI1 were required for life span extension and repression of the tumor suppressor p16(INK4). Furthermore, a RING finger deletion mutant that exhibited dominant negative activity induced p16(INK4) and premature senescence. Some presenescent cultures contained growth-arrested cells expressing high levels of p16(INK4) and were apparently arrested by a p53- and telomere-independent mechanism. BMI1 selectively extended the life span of these cultures.
Wang et al. (2004) showed that an E3 ubiquitin ligase complex, which they designated Polycomb repressive complex-1-like (PRC1L), specifically monoubiquitinates histone-2A (H2A; see 142711) at lys119. They found that PRC1L is composed of several PcG proteins, including RING1, RNF2 (608985), BMI1, and HPH2 (EDR2; 602979). Reduction of RNF2 expression resulted in a dramatic decrease in the level of ubiquitinated H2A in HeLa cells. Wang et al. (2004) proposed that H2A ubiquitination is linked to Polycomb silencing.
By analyzing proteins that immunoprecipitated with anti-CENPA (117139) antibodies from HeLa cell nuclear lysates, Obuse et al. (2004) showed that BMI1 associated with a centromeric complex, which also contained the major centromeric proteins CENPB (117140), CENPC (117141), CENPH (605607), CENPI (300065), and MIS12 (609178), and many others. Confocal microscopy showed that BMI1 transiently colocalized with centromeres during interphase in HeLa cells.
Guo et al. (2007) found that expression of MEL18 (PCGF2; 600346) negatively correlated with BMI1 in several human breast cancer cell lines and in a significant number of breast tumors. Overexpression of MEL18 in the MCF7 breast cancer cell line downregulated BMI1 and reduced the transformed phenotype. Furthermore, reduced BMI1 expression in MCF7 cells by MEL18 overexpression or by RNA interference was accompanied by downregulation of AKT (164730) activity. Overexpression of constitutively active AKT restored the malignant phenotype in MCF7 cells with reduced BMI1 expression. Guo et al. (2007) concluded that MEL18 acts as a tumor suppressor in breast cancer cells by repressing BMI1 expression and downregulating AKT activity.
To investigate the role of BMI1 in adult stem cell populations, Sangiorgi and Capecchi (2008) generated a mouse expressing a tamoxifen-inducible Cre from the Bmi1 locus. They found that Bmi1 is expressed in discrete cells located near the bottom of crypts in the small intestine, predominantly 4 cells above the base of the crypt (+4 position). Over time, these cells proliferate, expand, self-renew, and give rise to all the differentiated cell lineages of the small intestine epithelium. The induction of a stable form of beta-catenin (116806) in these cells was sufficient to rapidly generate adenomas. Moreover, ablation of Bmi1+ cells using a Rosa26 conditional allele, expressing diphtheria toxin, led to crypt loss. Sangiorgi and Capecchi (2008) concluded that their experiments identified Bmi1 as an intestinal stem cell marker in vivo. Unexpectedly, the distribution of Bmi1-expressing stem cells along the length of the small intestine suggested that mammals use more than 1 molecularly distinguishable adult stem cell subpopulation to maintain organ homeostasis.
Using RT-PCR and flow cytometric analysis, Heffner and Fearon (2007) found that Bmi1 expression increased in mouse Cd8 (see 186910)-positive T cells in an antigen dose- and time-dependent manner. Expression of Bmi1 could be reversed by removal of antigen or maintained by stimulation of Il2r (147730). Suppression of Bmi1 by lentivirally encoded short hairpin RNA inhibited proliferation of a mouse T-cell line and primary Cd8-positive T cells. Ectopic expression of Bmi1 enhanced the expansion of primary Cd8-positive T cells in vitro when stimulated by Il2 (147680) and Il7 (146660). Increased Bmi1 expression was detected after stimulation of naive Cd44-low (107269)/Cd8-positive T cells and memory Cd44-high/Klrg1 (604874)-negative/Cd8-positive T cells, but not after stimulation of Klrg1-positive/Cd8-positive T cells. Klrg1-positive/Cd8-positive T cells had elevated levels of p16Ink4a and p19Arf, products of the Cdkn2a gene (600160) that is transcriptionally repressed by Bmi1. Heffner and Fearon (2007) concluded that BMI1 is required for optimal proliferation of CD8-positive T cells and that T-cell receptor ligation causes its expression in naive and KLRG1-negative memory cells, but not in senescent, KLRG1-positive T cells.
Liu et al. (2009) demonstrated that cells derived from Bmi1 -/- mice have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species, and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1 -/- mice improve after either pharmacologic treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (CHEK2; 604373) deletion. Liu et al. (2009) concluded that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis, and that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.
Two principal epithelial stem cell pools exist in small intestine: columnar Lgr5 (606667)-expressing cells, which cycle rapidly and are present predominantly at the crypt base, and Bmi1-expressing cells, which reside largely above the crypt base. Using a human diphtheria toxin receptor (DTR) gene knocked into the Lgr5 locus, Tian et al. (2011) specifically ablated Lgr5-expressing cells in mice. They authors found that complete loss of the Lgr5-expressing cells did not perturb homeostasis of the epithelium, indicating that other cell types can compensate for the elimination of this population. After ablation of Lgr5-expressing cells, progeny production by Bmi1-expressing cells increased, indicating that Bmi1-expressing stem cells compensate for the loss of Lgr5-expressing cells. Indeed, lineage tracing showed that Bmi1-expressing cells gave rise to Lgr5-expressing cells, pointing to a hierarchy of stem cells in the intestinal epithelium. Tian et al. (2011) concluded that their results demonstrated that Lgr5-expressing cells are dispensable for normal intestinal homeostasis, and that in the absence of these cells, Bmi1-expressing cells can serve as an alternative stem cell pool. Tian et al. (2011) suggested that the Bmi1-expressing stem cells may represent both a reserve stem cell pool in case of injury to the small intestine epithelium and a source for replenishment of the Lgr5-expressing cells under nonpathologic conditions.
Using RNA pull-down and immunoprecipitation assays and deletion mapping, Hu et al. (2014) found that a central region of FAL1 (FALEC; 616092), a long noncoding RNA that showed amplification and upregulation in epithelial tumors and cancer cell lines, interacted directly with BMI1, a core subunit of PRC1. Knockdown and overexpression experiments suggested that interaction with FAL1 stabilized BMI1 against ubiquitination and proteasome-mediated degradation. The authors hypothesized that stabilization of BMI1 by FAL1 may further stabilize all of PRC1.
Using affinity purification in HEK293 cells and mass spectrometry, Bordeleau et al. (2014) identified UBAP2L (616472) as a BMI1-interacting protein. Immunoprecipitation analysis confirmed the interaction and showed that UBAP2L also interacted with RNF2. Expression of UBAP2L, like BMI1, was increased in leukemic stem cells (LSCs) from AML (601626) specimens with high, but not low, LSC frequency. Reducing mouse Ubap2l levels with short hairpin RNA resulted in lower progenitor and hematopoietic stem cell (HSC) activity. Bone marrow cells from conditional and knockout Ubap2l mice showed reduced repopulation activity, and Bmi1 overexpression partially restored this repopulation defect. Short hairpin RNA-mediated reduction of UBAP2L levels did not affect BMI1 or RNF2 levels in mouse or human cell lines, and Ubap2l was not involved in regulation of the Ink4a/Arf locus in mouse cells. Western blot analysis of HEK293 cell extracts showed that 2 distinct BMI1/RNF2 complexes exist, one containing UBAP2L and PHC1 (602978) and the other lacking these proteins. Bordeleau et al. (2014) proposed a model in which the UBAP2L-independent BMI1/RNF2 complex is involved in INK4A/ARF repression, whereas the UBAP2L/BMI1/RNF2/PHC1 complex operates independently of INK4A/ARF repression.
Lin et al. (2016) isolated lens epithelial stem/progenitor cells (LECs) in mammals and showed that Pax6 (607108) and Bmi1 are required for LEC renewal. The authors designed a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Their method preserved endogenous LECs and their natural environment maximally, and regenerated lenses with visual function.
Alkema et al. (1993) determined that the human BMI1 gene contains at least 10 exons. The murine Bmi1 gene contains 10 exons.
Crystal Structure
McGinty et al. (2014) crystallized the Polycomb repressive complex-1 (PRC1) ubiquitylation module, an E2-E3 enzyme complex composed of UBCH5C (602963) and the minimal RING1B (608985)-BMI1 ring heterodimer, bound to its nucleosome core particle substrate. The authors solved the structure at 3.3-angstrom resolution. The structure shows how a chromatin enzyme achieves substrate specificity by interacting with several nucleosome surfaces spatially distinct from the site of catalysis. McGinty et al. (2014) concluded that the structure revealed an unexpected role for the ubiquitin E2 enzyme in substrate recognition, and provides insight into how a related histone H2A E3 ligase, BRCA1 (113705), interacts with and ubiquitylates the nucleosome.
Alkema et al. (1993) assigned the human BMI1 gene to chromosome 10p13 by fluorescence in situ hybridization. The authors stated that the region 10p13 is known to be involved in translocations in various leukemias.
The protein encoded by the BMI1 gene has a domain of homology to a Drosophila protein encoded by a member of the Polycomb-group gene family, which is required to maintain the repression of homeotic genes that regulate the identities of Drosophila segments. The fact that mice lacking the BMI1 gene showed posterior transformations of the axial skeleton suggested that the gene may play a similar role in vertebrates. Alkema et al. (1995) found that transgenic mice overexpressing the Bmi1 protein showed the opposite phenotype, namely a dose-dependent anterior transformation of vertebral identity. The anterior expression boundary of the Hoxc5 (142973) gene was shifted in the posterior direction, indicating that Bmi1 is involved in the repression of Hox genes. Thus, BMI1 appears to be a member of a vertebrate Polycomb complex that regulates segmental identity by repressing HOX genes throughout development.
Molofsky et al. (2003) showed that in the mouse, Bmi1 is required for the self-renewal of stem cells in the peripheral and central nervous systems but not for their survival or differentiation. The reduced self-renewal of Bmi1-deficient neural stem cells led to their postnatal depletion. In the absence of Bmi1, the cyclin-dependent kinase inhibitor gene P16(Ink4a) (600160) was upregulated in neural stem cells, reducing the rate of proliferation. P16(Ink4a) deficiency partially reversed the self-renewal defect in Bmi1 null neural stem cells. This conserved requirement for Bmi1 to promote self-renewal and to repress p16(Ink4a) expression suggested that a common mechanism regulates the self-renewal and postnatal persistence of diverse types of stem cells. Restricted neural progenitors from the gut and forebrain proliferated normally in the absence of Bmi1. Thus, Molofsky et al. (2003) concluded that BMI1 dependence distinguishes stem cell self-renewal from restricted progenitor proliferation in these tissues.
Kranc et al. (2003) found that Cited2 (602937) null mouse fibroblasts showed reduced proliferation that was associated with reduced Bmi1 and Mel18 (600346) expression, and increased Ink4a/Arf expression. Bmi1- and Mel18-expressing retroviruses enhanced the proliferation of Cited2 null fibroblasts, indicating that they function downstream of Cited2. Kranc et al. (2003) concluded that CITED2 controls the expression of INK4A/ARF and fibroblast proliferation, at least in part, via the polycomb-group genes BMI1 and MEL18.
Park et al. (2003) found that adult and fetal mouse and adult human HSCs express the protooncogene Bmi1. The number of HSCs in fetal liver of Bmi1 -/- mice was normal. In postnatal Bmi1 -/- mice, the number of HSCs was markedly reduced. Transplanted fetal liver and bone marrow cells obtained from Bmi1 -/- mice were able to contribute only transiently to hematopoiesis. There was no detectable self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi1 null mice. Gene expression analysis revealed that the expression of stem cell-associated genes, cell survival genes, transcription factors, and genes modulating proliferation, including p16(Ink4a) and p19(Arf) (see 600160), was altered in bone marrow cells of the Bmi1 null mice. Expression of p16(Ink4a) and p19(Arf) in normal HSCs resulted in proliferative arrest and p53 (191170)-dependent cell death, respectively. Park et al. (2003) concluded that Bmi1 is essential for the generation of self-renewing adult HSCs.
Leung et al. (2004) demonstrated that BMI1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1 null mice, Leung et al. (2004) demonstrated a crucial role for Bmi1 in clonal expansion of granule cell precursors both in vivo and in vitro. Deregulated proliferation of these progenitor cells, by activation of the Sonic hedgehog (SHH; 600725) pathway, leads to medulloblastoma development (see 155255). Leung et al. (2004) also demonstrated linked overexpression of BMI1 and Patched (601309), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 (165220) in cerebellar granule cell cultures, Leung et al. (2004) concluded that their findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for BMI1-containing polycomb complexes in proliferation of cerebellar precursor cells.
Chagraoui et al. (2006) found that knockdown of E4f1 (603022) levels by RNA interference was sufficient to rescue the clonogenic and repopulating ability of Bmi1 -/- mouse hematopoietic cells up to 3 months posttransplantation. They concluded that E4F1 is a key modulator of BMI1 activity in primitive hematopoietic cells.
Dovey et al. (2008) found that loss of Bmi1 decreased the number and progression of lung tumors at a very early point in an oncogenic Kras (190070)-initiated mouse model of lung cancer. This correlated with a defect in the ability of Bmi1-deficient putative bronchioalveolar stem cells to proliferate in response to the oncogenic stimulus and depended, in part, on p19(Arf).
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