Written | 2010-01 | Malene Krag Kjeldsen, Karen Dybkaer, Jinghua Liu, Finn Skou Pedersen |
Department of Haematology, Medical Center Aalborg Hospital Science, Innovation Center AHSIC, Sdr Skovvej 15, Aarhus University Hospital, DK-9000 Aalborg, Denmark (MKK, KD); Department of Molecular Biology, CF Mollers Alle 3, 1.130, Aarhus University, DK-8000 Arhus C, Denmark (JL, FSP) |
Identity |
HGNC (Hugo) | BACH2 |
HGNC Alias symb | BTBD25 |
HGNC Previous name | "BTB and CNC homology 1, basic leucine zipper transcription factor 2" |
LocusID (NCBI) | 60468 |
Atlas_Id | 741 |
Location | 6q15 [Link to chromosome band 6q15] |
Location_base_pair | Starts at 89926528 and ends at 90296843 bp from pter ( according to GRCh38/hg38-Dec_2013) [Mapping BACH2.png] |
Local_order | Reverse strand. |
Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
ARHGAP6 (Xp22.2) / BACH2 (6q15) | BACH2 (6q15) / BCL2L1 (20q11.21) | BACH2 (6q15) / MAP3K7 (6q15) | |
BACH2 (6q15) / ZDHHC13 (11p15.1) | NUDCD2 (5q34) / BACH2 (6q15) | RAG2 (11p12) / BACH2 (6q15) | |
RNGTT (6q15) / BACH2 (6q15) | STPG1 (1p36.11) / BACH2 (6q15) | TBC1D22A (22q13.31) / BACH2 (6q15) | |
DNA/RNA |
Description | DNA: NCBI Reference Sequence: NC_000006.11; 370316 bp DNA; BACH2 consists of 9 exons and 8 intervening introns. RNA: NCBI Reference Sequence: NM_021813.2; 9215 bp mRNA. |
Transcription | Transcription produces at least four alternative spliced variants. |
Pseudogene | By FISH, Sasaki et al. (2000) mapped the BACH2 gene to chromosome 6q15. Southern blot analysis determined that BACH2 is a single-copy gene (Sasaki et al., 2000). |
Protein |
Description | Reference sequence for BACH2 protein: NP_068585.1. BACH2 contains 841 amino acid residues with a molecular weight of 92536 Da. BACH2 belongs to the bZIP family and CNC subfamily. BACH2 contains a BTB domain for protein interaction in the N-terminal region starting at amino acid residue 37 to 103. In the C-terminus from amino acid residue 651 to amino acid residue 666 a basic DNA binding domain, followed by a hydrophobic leucine zipper domain ranging from amino acid residue 674 to 695 responsible for dimerisation. The four alternative spliced variants generate four different proteins: 1) BACH2-003, transcript ID: ENST00000257749 and protein ID: ENSP00000257749. This transcript contains all 9 exons and have the full length transcript at 9215 bps and a full length protein with 841 aa. 2) BACH2-005, transcript ID: ENST00000343122 and protein ID: ENSP00000345642. This transcript contains 7 exons (1, 4, 5, 6, 7, 8, 9) resulting in a transcript with 3981 bps and a protein with 841 aa. 3) BACH2-002, transcript ID: ENST00000406998 and protein ID: ENSP00000384145. This transcript contains only 4 alternative exons (1, 4, 5, 6) producing a transcript at 780 bps and a protein with 81 aa. This alternative protein only contains the BTB domain. 4) BACH2-007, transcript ID : ENST00000453877 and protein ID: ENSP00000397668. This transcript contains only 5 alternative exons (1, 2, 4, 5, 6), producing a transcript at 868 bps and 81 aa. This alterniative protein only contains the BTB domain. Liu et al. have, in mice, identified an alternative promoter and new isoforms of BACH2 by using murine insertional mutagenesis (Liu et al., 2009). Related proteins: |
Expression | BACH2 is expressed mainly in B-lymphoid cells and in the fetal brain (Muto et al., 1998; Hoshino and Igarashi, 2002). During B cell differentiation BACH2 is expressed from the pro-B cell to the mature B-cell stages but is absent in the plasma cell stage (Igarashi et al., 2007). Its expression is also silenced in primary plasma cells (our unpublished observation). BACH2 is expressed in umbilical cord blood CD4+ T cells (Lesniewski et al., 2008). |
Localisation | BACH2 is predominantly cytoplasmic and migrates to the nucleus upon oxidative stress where it functions as a proapoptotic factor (Muto et al., 2002; Hoshino et al., 2000). |
Function | BACH2 protein is a transcriptional repressor or activator. BACH2 forms heterodimers with small Maf oncoproteins (MafF, MafG, MafK) through the BTB domain. It binds to Maf recognition elements (MARE) through the DNA binding domain bZIP. It plays important roles in coordinating transcription activation and repression by MAFK (by similarity) (Oyake et al., 1996). BACH2 in B-cell differentation: Neuronal differentiation: Immune response: |
Homology | HomoloGene (NCBI) BACH2 conserved in Euteleostomi. Genes identified as putative homologs: NP_068585.1 BACH2 Homo sapiens XP_539044.2 BACH2 Canis lupus familiaris XP_618496.2 BACH2 Bos taurus XP_232858.3 RGD1562865 Rattus norvegicus XP_419833.2 BACH2 Gallus gallus XP_682933.2 bach2 Danio rerio |
Mutations |
Note | There are 11 SNPs in coding regions of human BACH2 of which 4 are encoding missense protein residues (NCBI dbSNP). Bach2 is considered a B-cell specific tumor suppressor since loss of heterozygosity (LOH) is frequently observed for non-hodgkin lymphomas (Sasaki et al., 2000). High throughput screens using retroviral and transposon insertion into mouse models have identified BACH2 as a common insertion site (CIS) (http://rtcgd.abcc.ncifcrf.gov/). BACH2 expression is in these models disrupted or activated in the resulting B cell tumours. Homozygous null mice display impaired B cell differentiation and reduced B cell numbers. |
Implicated in |
Note | |
Entity | Diffuse large B-cell lymphoma (DLBCL) |
Note | BACH2 expression was immunohistochemically examined for 108 DLBCL patients and for 2/3 of cases staining intensity in the cytoplasm of the tumor cells was weaker than that in the endothelial cells in the same specimens (Sakane-Ishikawa et al., 2005). The translocation between the Bcl-2 and the immunoglobulin heavy-chain (IgH) gene, t(14;18)(q21;q34), is a common genetic alteration in follicular and DLBCL lymphomas, bringing the antiapoptotic Bcl-2 gene under regulation of the active IgH promoter in B-cells. This translocation should result in an upregulation of Bcl-2 due to the activity of the IgH promoter in B-cells. Green et al. demonstrated that patients with t(14;18) and a high expression of BACH2 had significantly lower Bcl-2 expression from the t(14;18) translocation (Green et al., 2009). |
Disease | DLBCL, a lymphoma entity characterised by an agressive malignancy of mature B-lymphocytes, is the most common type of B-NHL accounting for 30-40%. Bach2 is a B-cell specific tumor suppressor and relatively high frequencies of loss of heterozygosity (LOH), 20% in 25 cases, was detected for Bach2 (Sasaki et al., 2000). |
Prognosis | Most patients respond initially to chemotherapy, fewer than half of the patients achieve a durable remission. At present, the International Prognostic Index (IPI) is the most widely used for prediction of outcome in patients with aggresive NHL. It incorporates patient age performance status, serum lactate dehydrogenase (LDH), clinical stage, and the number of extranodal lesions. Bach2 expression level has proven to be a useful marker to predict disease-free and overall survival of patients with DLBCL, where a favorable prognosis is correlated with a high expression level of Bach2 protein (Sakane-Ishikawa et al., 2005), perhaps because over-expression of Bach2 increased cellular toxicity of anticancer drugs that generate reactive oxygen species (Kamio et al., 2003). |
Entity | Chronic myeloid leukemia (CML) |
Note | Comparison of the mRNA profile of a CML cell line, BV173, before and after imatinib treatment revealed an accumulation of BACH2 mRNA upon BCR-ABL kinase inhibition (Vieira et al., 2001). This up-regulation of BACH2 by imatinib was seen in lymphoid BCR-ABL1-positive cell lines, as well as in CD34+ cells from CML patients, but not in myeloid BCR-ABL1-positive cell lines. However, the relationship between the regulation of BACH2 and higher order nuclear structure in CML and human B cells remains unclear (Vieira et al., 2001; Yoshida et al., 2006). |
Disease | CML is a myeloproliferative disorder of the hematopoietic stem cell caused by a t(9;22)(q34;q11) translocation that generates the Philadelphia (Ph) chromosome. This translocation result in the expression of the fusion oncoprotein, Bcr-Abl, with uncontrolled tyrosine kinase activity. Bcr-Abl phsphorylates several substrates that activate multiple signaling pathways, including Ras, signal transducer and activator of transcription-5 (STAT-5), Janus kinase 2 (Jak-2) and others. This abnormal signaling leads to increased proliferation, reduced adhesion to the bone marrow stroma and extracellular matrix, and inhibition of the apoptotic response to mutagenic stimuli, giving rise to the malignant phenotype of CML (Yoshida et al., 2006). |
Entity | Burkitt's lymphoma |
Note | Epstein-Barr virus is an oncogenic virus, present in Burkitt's lymphoma cells. The Raji cell line (Burkitt's lymphoma) has no BACH2 expression and enforced BACH2 expression generates a marked reduction of clonogenic activity (Sasaki et al., 2000). Takakuwa and co-workers demonstrated that the EBV chromosome was present in intron 1 of the BACH2 gene located on chromosome 6q15. As BACH2 is a putative tumour suppressor gene, they suggest that loss of BACH2 might contribute to lymphomagenesis (Takakuwa et al., 2004). |
Entity | Ovarian cancer |
Note | Dysregulated androgen response in ovarian cancer results in transcriptional upregulation of BACH2 and acetylchrolinesterase. Both cytoplasmic BACH2 and acetylcholinesterase immunostaining were significantly increased in ovarian cancer relative to benign cases. Accumulation of nuclear BACH2 correlated with decreased time to disease recurrence (Motamed-Khorasani et al., 2007). |
Entity | Diabetes type 1 |
Note | Type 1 diabetes is a common multifactorial with a strong genetic component. Genome wide association studies reveal that BACH2 is associated with Type 1 diabetes (Grant et al., 2009; Cooper et al., 2008). |
Bibliography |
Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. |
Cooper JD, Smyth DJ, Smiles AM, Plagnol V, Walker NM, Allen JE, Downes K, Barrett JC, Healy BC, Mychaleckyj JC, Warram JH, Todd JA. |
Nat Genet. 2008 Dec;40(12):1399-401. Epub 2008 Nov 2. |
PMID 18978792 |
Follow-up analysis of genome-wide association data identifies novel loci for type 1 diabetes. |
Grant SF, Qu HQ, Bradfield JP, Marchand L, Kim CE, Glessner JT, Grabs R, Taback SP, Frackelton EC, Eckert AW, Annaiah K, Lawson ML, Otieno FG, Santa E, Shaner JL, Smith RM, Skraban R, Imielinski M, Chiavacci RM, Grundmeier RW, Stanley CA, Kirsch SE, Waggott D, Paterson AD, Monos DS; DCCT/EDIC Research Group, Polychronakos C, Hakonarson H. |
Diabetes. 2009 Jan;58(1):290-5. Epub 2008 Oct 7. |
PMID 18840781 |
High levels of BACH2 associated with lower levels of BCL2 transcript abundance in t(14;18)(q21;q34) translocation positive non-Hodgkin's lymphoma. |
Green M, Gandhi MK, Camilleri E, Marlton P, Lea R, Griffiths L. |
Leuk Res. 2009 May;33(5):731-4. Epub 2008 Oct 16. |
PMID 18929412 |
The role of Bach2 in nucleic acid-triggered antiviral innate immune responses. |
Hong SW, Kim S, Lee DK. |
Biochem Biophys Res Commun. 2008 Jan 18;365(3):426-32. Epub 2007 Nov 6. |
PMID 17991429 |
Expression of the oxidative stress-regulated transcription factor bach2 in differentiating neuronal cells. |
Hoshino H, Igarashi K. |
J Biochem. 2002 Sep;132(3):427-31. |
PMID 12204112 |
Oxidative stress abolishes leptomycin B-sensitive nuclear export of transcription repressor Bach2 that counteracts activation of Maf recognition element. |
Hoshino H, Kobayashi A, Yoshida M, Kudo N, Oyake T, Motohashi H, Hayashi N, Yamamoto M, Igarashi K. |
J Biol Chem. 2000 May 19;275(20):15370-6. |
PMID 10809773 |
Architecture and dynamics of the transcription factor network that regulates B-to-plasma cell differentiation. |
Igarashi K, Ochiai K, Muto A. |
J Biochem. 2007 Jun;141(6):783-9. (REVIEW) |
PMID 17569706 |
B-cell-specific transcription factor BACH2 modifies the cytotoxic effects of anticancer drugs. |
Kamio T, Toki T, Kanezaki R, Sasaki S, Tandai S, Terui K, Ikebe D, Igarashi K, Ito E. |
Blood. 2003 Nov 1;102(9):3317-22. Epub 2003 Jun 26. |
PMID 12829606 |
A combinatorial code for gene expression generated by transcription factor Bach2 and MAZR (MAZ-related factor) through the BTB/POZ domain. |
Kobayashi A, Yamagiwa H, Hoshino H, Muto A, Sato K, Morita M, Hayashi N, Yamamoto M, Igarashi K. |
Mol Cell Biol. 2000 Mar;20(5):1733-46. |
PMID 10669750 |
Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells. |
Lesniewski ML, Haviernik P, Weitzel RP, Kadereit S, Kozik MM, Fanning LR, Yang YC, Hegerfeldt Y, Finney MR, Ratajczak MZ, Greco N, Paul P, Maciejewski J, Laughlin MJ. |
Leukemia. 2008 Dec;22(12):2201-7. Epub 2008 Sep 4. |
PMID 18769450 |
Identification of novel Bach2 transcripts and protein isoforms through tagging analysis of retroviral integrations in B-cell lymphomas. |
Liu J, Sorensen AB, Wang B, Wabl M, Nielsen AL, Pedersen FS. |
BMC Mol Biol. 2009 Jan 21;10:2. |
PMID 19159451 |
Differentially androgen-modulated genes in ovarian epithelial cells from BRCA mutation carriers and control patients predict ovarian cancer survival and disease progression. |
Motamed-Khorasani A, Jurisica I, Letarte M, Shaw PA, Parkes RK, Zhang X, Evangelou A, Rosen B, Murphy KJ, Brown TJ. |
Oncogene. 2007 Jan 11;26(2):198-214. Epub 2006 Jul 10. |
PMID 16832351 |
Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3' enhancer. |
Muto A, Hoshino H, Madisen L, Yanai N, Obinata M, Karasuyama H, Hayashi N, Nakauchi H, Yamamoto M, Groudine M, Igarashi K. |
EMBO J. 1998 Oct 1;17(19):5734-43. |
PMID 9755173 |
The transcriptional programme of antibody class switching involves the repressor Bach2. |
Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E, Ikebe D, Yamamoto M, Igarashi K. |
Nature. 2004 Jun 3;429(6991):566-71. Epub 2004 May 19. |
PMID 15152264 |
Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells. |
Ochiai K, Katoh Y, Ikura T, Hoshikawa Y, Noda T, Karasuyama H, Tashiro S, Muto A, Igarashi K. |
J Biol Chem. 2006 Dec 15;281(50):38226-34. Epub 2006 Oct 17. |
PMID 17046816 |
Regulation of the plasma cell transcription factor Blimp-1 gene by Bach2 and Bcl6. |
Ochiai K, Muto A, Tanaka H, Takahashi S, Igarashi K. |
Int Immunol. 2008 Mar;20(3):453-60. Epub 2008 Feb 5. |
PMID 18256039 |
Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. |
Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, Yamamoto M, Igarashi K. |
Mol Cell Biol. 1996 Nov;16(11):6083-95. |
PMID 8887638 |
Prognostic significance of BACH2 expression in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group. |
Sakane-Ishikawa E, Nakatsuka S, Tomita Y, Fujita S, Nakamichi I, Takakuwa T, Sugiyama H, Fukuhara S, Hino M, Kanamaru A, Soma T, Tsukaguchi M, Igarashi K, Kanakura Y, Aozasa K; Osaka Lymphoma Study Group. |
J Clin Oncol. 2005 Nov 1;23(31):8012-7. |
PMID 16258099 |
Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15. |
Sasaki S, Ito E, Toki T, Maekawa T, Kanezaki R, Umenai T, Muto A, Nagai H, Kinoshita T, Yamamoto M, Inazawa J, Taketo MM, Nakahata T, Igarashi K, Yokoyama M. |
Oncogene. 2000 Aug 3;19(33):3739-49. |
PMID 10949928 |
Bach2 is involved in neuronal differentiation of N1E-115 neuroblastoma cells. |
Shim KS, Rosner M, Freilinger A, Lubec G, Hengstschlager M. |
Exp Cell Res. 2006 Jul 15;312(12):2264-78. Epub 2006 Apr 24. |
PMID 16631738 |
Integration of Epstein-Barr virus into chromosome 6q15 of Burkitt lymphoma cell line (Raji) induces loss of BACH2 expression. |
Takakuwa T, Luo WJ, Ham MF, Sakane-Ishikawa F, Wada N, Aozasa K. |
Am J Pathol. 2004 Mar;164(3):967-74. |
PMID 14982850 |
Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene. |
Vieira SA, Deininger MW, Sorour A, Sinclair P, Foroni L, Goldman JM, Melo JV. |
Genes Chromosomes Cancer. 2001 Dec;32(4):353-63. |
PMID 11746976 |
Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1. |
Yoshida C, Yoshida F, Sears DE, Hart SM, Ikebe D, Muto A, Basu S, Igarashi K, Melo JV. |
Blood. 2007 Feb 1;109(3):1211-9. Epub 2006 Oct 3. |
PMID 17018862 |
Citation |
This paper should be referenced as such : |
Kjeldsen, MK ; Dybkaer, K ; Liu, J ; Pedersen, FS |
BACH2 (BTB, CNC homology 1, basic leucine zipper transcription factor 2) |
Atlas Genet Cytogenet Oncol Haematol. 2010;14(10):930-933. |
Free journal version : [ pdf ] [ DOI ] |
Other Leukemias implicated (Data extracted from papers in the Atlas) [ 2 ] |
t(6;20)(q15;q11.2) BACH2/BCL2L1
t(6;11)(q15;p15) BACH2/ZDHHC13 |
Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
t(6;22)(q15;q13) TBC1D22A/BACH2
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External links |
REVIEW articles | automatic search in PubMed |
Last year publications | automatic search in PubMed |
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