BMI1 (BMI1 polycomb ring finger oncogene)

2009-03-01   Lina Han , Szabolcs Fatrai , Jan Jacob Schuringa 

Department of Hematology, University Medical Center Groningen, Hanzeplein 1, 9700 RB, The Netherlands

Identity

HGNC
LOCATION
10p12.2
IMAGE
Atlas Image
LOCUSID
ALIAS
FLVI2/BMI1,PCGF4,RNF51,flvi-2/bmi-1
FUSION GENES

DNA/RNA

Atlas Image

Description

DNA size: 10.04 kb with 10 exons.
The BMI1 gene is a highly conserved gene. The cDNA shows 86% identity to the mouse sequence.

Transcription

mRNA size: 3199 bp.

Proteins

Note

326 amino acids
Molecular weight of the protein: 36949 Da.
Atlas Image

Description

The ring finger domain is a cysteine-rich domain that binds two atoms of zinc and plays a key role in the process of ubiquitination. In hematopoietic stem cells BMI1 interacts with a proliferation inhibitor E4F through the IE4F site.

Expression

Hematopoietic system: BMI1 is expressed in adult and embryonic fetal liver hematopoietic stem cells (HSC). During hematopoietic development the expression of BMI1 declines. Bmi1-/- mice are born with a hypocellular bone marrow, they have normal number of myeloid cells in the peripheral blood but lower number of lymphocytes. In the bone marrow of Bmi1-/- mice the total HSC number is decreased with 10-fold and transplanted bone marrow and fetal liver cells were able to contribute to hematopoiesis only transiently. Bmi1-depleted mice die within two months after birth. Adult HSCs from Bmi1-/- mice lack self-renewal potential. Furthermore, expression of stem cell-associated genes, cell survival genes, transcription factors and genes modulating proliferation was altered in the bone marrow cells. BMI1 overexpression was studied in transgenic mice and human CB models. In these mouse models 14% of the mice developed lymphoma. BMI1 overexpression in CD34+ cord blood cells resulted in long term maintenance and self-renewal of human hematopoietic stem and progenitor cells. These cells engrafted more efficiently in NOD-SCID mice and gave a rise to secondary engraftment.
Nervous system: BMI1 is required for neural stem cell self-renewal but it does not influence their survival and differentiation. BMI1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. The absence of BMI1 was related to the low level of p16 Ink4 as well as to low proliferation rate of neural stem cells. BMI1-deficient mice develop balance disorders, tremor, behavior disorders and they have a severe reduction in total postnatal brain mass.
Fibroblasts: In BMI1-deficient primary mouse embryonic fibroblast cell cycle progression to S phase was impaired and cells entered early senescence.

Localisation

In nucleus and in the cytoplasm.

Function

BMI1 is a member of the Polycomb group (PcG) genes, which are transcriptional repressors that play essential roles in the maintenance of appropriate gene expression during development. Two distinct multiprotein PcG complexes have been identified, the Polycomb Repression Complex (PRC) 1 and PRC2. The PRC2 complex is involved in initiation of silencing and contains histone deacetylases and methyltransferases that can methylate H3 lysine 9 and 27 (H3K27). Deletion of PRC2 genes in mice results in embryonic lethality, emphasizing their importance in development. PRC1 is implicated in stable maintenance of gene repression and recognizes the methylation marks set by PRC2. Mice mutant for most PRC1 genes survive until birth as result of partial functional redundancy provided by their homologues, but developmental defects do arise thereafter as is e.g. the case in the hematopoietic compartment after deletion of BMI1. Targeted deletion of BMI1 has shown that although the numbers of fetal liver-derived HSCs is normal in these mice, their proliferative and self-renewal capacity is severely impaired. In adult BMI1-deficient mice, the HSCs are less frequent and display an impaired competitive repopulation capacity. Gain-of-function studies demonstrated enhanced self-renewal of murine HSC and with a shift in balance towards more symmetric stem cell divisions. Constitutive expression of BMI1 in human cord blood cells results in prolonged maintenance of the stem cell pool and enhances self-renewal of human stem and progenitor cells. BMI1 is potent negative regulator of the Ink4a/Arf locus in embryonic fibroblasts. This locus encodes the cell cycle regulators and tumor suppressor p16 and p19/p14. Increased expression of these genes was observed in the BMI1-deficient mice. However, INK4A/ARF-independent BMI1-targets must exist as well since overexpression of BMI1 in p16/p19-deficient cells still altered HSC self-renewal phenotypes.

Mutations

Note

A mutation in BMI1 that results in a cysteine into tyrosine substitution at position 18 within the RING domain has been identified, which is associated with a decrease in BMI1 expression levels and elevated ubiquitination.

Implicated in

Entity name
Hematological malignancies
Disease
BMI1 overexpression has been demonstrated in several hematological malignancies, mainly including mantle cell lymphoma, myeloid dysplastic syndrome (MDS), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML).
Prognosis
In general, high BMI1 expression levels are associated with a poor prognosis and increased aggressiveness of the tumors. In CML, the level of BMI1 at diagnosis correlated with time to transformation to blast crisis. In MDS, patients with RA and RARS with a higher percentage of BMI1-positive cells showed disease progression to RAEB. Intriguingly, in CML post allo-SCT, high BMI1 at diagnosis predicts better overall survival, which might be ascribed to the neutralized effects against BMI1 by an immune response in donor cells.
Cytogenetics
Different chromosomal translocations involving the 10p11-13 region have also been identified in infant leukemias, occurring in children < 12 months of age and T cell lymphoproliferative disorders, including mainly adult T cell leukemia/lymphomas and occasional cutaneous T cell lymphomas. It was demonstrated that BMI1 was overexpressed with MEIS1 in 11q23 (MLL) rearrangements, suggesting that p16/p19 suppression maybe involved in MLL-associated leukemia.
Oncogenesis
See below.
Entity name
Solid tumors
Disease
BMI1 overexpression was implicated in various solid tumors, including ovarian cancer, bladder cancer, squamous cell carcinoma, prostate cancer, breast carcinomas, non-small-cell lung cancer and GI cancer.
Prognosis
The oncogenic role of the BMI1 activation may contribute to progression of many types of solid tumors. The median survival is 46 months and 5-year survival is 37.5% in BMI1/EZH2-positive prostate cancer patients after radical prostatectomy (The 5-year survival is 72.4% in BMI1/EZH2-negative prostate cancer patients). But in breast cancer, increased BMI1 expression is associated with a good prognosis, which might be because BMI1 overexpression correlates with higher ER expression and lower TP53 mutations.
Oncogenesis
See below.
Entity name
Neural stem cells renewal
Note
BMI1 promotes the maintenance of adult neural stem cells (NSCs) by repressing the cyclin-dependent kinase inhibitors, p16Ink4a and p19ARF. Recent study showed that BMI1 was also important for NSCs in the embryo, using lentiviral-delivered shRNAs in vitro and in vivo. These defects caused by BMI1 downregulation were unexpectedly mediated by p21.
Oncogenesis
Gene-profiling studies show that BMI-/- HSC displayed altered expression of multiple genes important for stem cell fate decisions. The tumor suppressor locus p16Ink4a/p19ARF is one of the important targets that is repressed by BMI1. The p16Ink4a protein blocks the cyclinD-CDK complexes by binding directly to CDK4 and CDK6, enabling p21CIP1 and p27KIP1 to associate with and inhibit cyclin E-CDK2 and cyclin A-CDK2, which results the hypophosphorylated pRb. The E2F transcription factors will be sequestered and their target genes will be repressed, ultimately leading to G1-phase cell cycle arrest, senescence, or apoptosis. p19ARF binds to MDM2 and inhibits its ubiquitin ligase activity, resulting in activation of p53 target genes, including Wig1 and p21, leading to cell cycle arrest and apoptosis. Furthermore, cells might undergo apoptosis as a result of downregulated apoptosis inhibitor AI-6 in the absence of BMI1. BMI1 was also demonstrated to upregulate the human telomerase RT gene (hTERT), which might also be relevant for the self-renewal ability of HSCs or LSCs.
Deregulated Hox gene expression caused by chromosomal translocations and MLL rearrangements, is involved in some types of leukemia. The skeletal defects of PcG mutant mice revealed PcG genes as Hox gene regulators. Knockout of BMI1 results in alterations in Hox gene expression, with 12 Hox genes significantly upregulated (for example, HoxA7-HoxA13 ; HoxC10-HoxC13) and 13 downregulated (for example, HoxA1-HoxA4 ). This study demonstrated that BMI1 and RING1A play important roles in H2A ubiquitylation and Hox gene silencing.
Overexpression of BMI1 is involved in tumor development and is used as an important marker for predicting prognosis. The mechanisms regulating BMI1 expression are not fully elucidated yet. In AML, BMI1 was demonstrated to be a direct target gene of SALL4, a zinc-finger transcription factor, which is expressed constitutively in human leukemia cell lines and primary AML cells. High levels of H3-K4 trimethylation and H3-K79 dimethylation were observed in the SALL4 binding region of the BMI1promoter. In normal and malignant human mammary stem cells activation of hedgehog signaling increases BMI1 expression and BMI1 overexpression promotes mammary stem cell self-renewal and proliferation. In CML, it was suggested that BMI1 was positively regulated by BCR-ABL as well as by additional posttranscriptional modification in the course of the disease progression.
Chromatin association and dissociation of BMI1 was also studied. BMI1 can be phosphorylated by 3pk (MAPKAP kinase 3), a convergence point downstream of activated ERK and p38 signaling pathways which are implicated in differentiation and developmental processes. BMI1 phosphorylation results in dissociation of BMI1 from chromatin, followed by de-repression of target genes.

Bibliography

Pubmed IDLast YearTitleAuthors
159649952005Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice.Bruggeman SW et al
168829842006E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells.Chagraoui J et al
19040091991Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice.Haupt Y et al
84145191993bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis.Haupt Y et al
124829902003Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1.Itahana K et al
155891722004Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1.Iwama A et al
99236791999The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus.Jacobs JJ et al
150291992004Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas.Leung C et al
159649942005Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways.Molofsky AV et al
127149712003Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.Park IK et al
181564892008Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1.Rizo A et al
79267651994Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene.van der Lugt NM et al

Other Information

Locus ID:

NCBI: 648
MIM: 164831
HGNC: 1066
Ensembl: ENSG00000168283

Variants:

dbSNP: 648
ClinVar: 648
TCGA: ENSG00000168283
COSMIC: BMI1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000168283ENST00000376663P35226
ENSG00000168283ENST00000416820Q5T8Z6
ENSG00000168283ENST00000442508Q5T8Z4
ENSG00000168283ENST00000443519Q5T8Z2

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
SUMOylation of DNA damage response and repair proteinsREACTOMER-HSA-3108214
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
SUMOylation of RNA binding proteinsREACTOMER-HSA-4570464

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
173444142007The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells.350
159313892005Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer.297
208183892010Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition.227
150291992004Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas.176
242923922014Self-renewal as a therapeutic target in human colorectal cancer.165
198846592009The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells.157
124829902003Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1.133
196056262009BMI1 sustains human glioblastoma multiforme stem cell renewal.114
121834332002The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells.113
222528872012Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences.110

Citation

Lina Han ; Szabolcs Fatrai ; Jan Jacob Schuringa

BMI1 (BMI1 polycomb ring finger oncogene)

Atlas Genet Cytogenet Oncol Haematol. 2009-03-01

Online version: http://atlasgeneticsoncology.org/gene/807/bmi1