BCL9

BCL9, together with its paralogue gene BCL9L (BCL9 like or BCL9.2), have been extensively studied for their role as transcriptional beta-catenin cofactors, fundamental for the transcription of Wnt target genes.{{cite journal |vauthors=Mosimann C, Hausmann G, Basler K |title=Beta-catenin hits chromatin: regulation of Wnt target gene activation |journal=Nature Reviews. Molecular Cell Biology |volume=10 |issue=4 |pages=276–286 |date=April 2009 |pmid=19305417 |doi=10.1038/nrm2654 |s2cid=7602580}}

Recent work, using the mouse (Mus musculus) and zebrafish (Danio rerio) as model organisms, identified an ancient role of BCL9 and BCL9L as key factors required for cardiac development.{{cite journal |vauthors=Cantù C, Felker A, Zimmerli D, Prummel KD, Cabello EM, Chiavacci E, Méndez-Acevedo KM, Kirchgeorg L, Burger S, Ripoll J, Valenta T, Hausmann G, Vilain N, Aguet M, Burger A, Panáková D, Basler K, Mosimann C |display-authors=6 |title=Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling |journal=Genes & Development |volume=32 |issue=21–22 |pages=1443–1458 |date=November 2018 |pmid=30366904 |pmc=6217730 |doi=10.1101/gad.315531.118 |ref=2018 Cantù et al.; Published by Cold Spring Harbor Laboratory Press}} This work emphasises the tissue-specific nature of the Wnt/β-catenin mechanism of action, and implicates alterations in BCL9 and BCL9L in human congenital heart defects.

BCL9 and BCL9L have been shown to take part in other tissue-specific molecular mechanisms, showing that their role in the Wnt signaling cascade is only one aspect of their mode of action.{{cite journal |vauthors=Cantù C, Zimmerli D, Hausmann G, Valenta T, Moor A, Aguet M, Basler K |title=Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development |journal=Genes & Development |volume=28 |issue=17 |pages=1879–1884 |date=September 2014 |pmid=25184676 |pmc=4197948 |doi=10.1101/gad.246140.114}}

The conserved homology domain HD1 of BCL9 (and BCL9L) has recently been shown to be interacting with TBX3 in the context of intestinal carcinogenesis; this interaction mediates some tissue-specific signalling functions of the protein.{{cite journal |vauthors=Zimmerli D, Borrelli C, Jauregi-Miguel A, Söderholm S, Brütsch S, Doumpas N, Reichmuth J, Murphy-Seiler F, Aguet M, Basler K, Moor AE, Cantù C |display-authors=6 |title=TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex |journal=eLife |volume=9 |date=August 2020 |pmid=32808927 |pmc=7434441 |doi=10.7554/eLife.58123 |doi-access=free}}

BCL9 is associated with B-cell acute lymphoblastic leukemia. It may be a target of translocation in B-cell malignancies with abnormalities of 1q21. The overexpression of BCL9 may be of pathogenic significance in B-cell malignancies.

BCL9 and BCL9L are potential clinical targets for human cancers; for instance, the gene expression changes that they promote is associated with a poor outcome in colorectal cancer.{{cite journal |vauthors=Moor AE, Anderle P, Cantù C, Rodriguez P, Wiedemann N, Baruthio F, Deka J, André S, Valenta T, Moor MB, Győrffy B, Barras D, Delorenzi M, Basler K, Aguet M |display-authors=6 |title=BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer |journal=eBioMedicine |volume=2 |issue=12 |pages=1932–1943 |date=December 2015 |pmid=26844272 |pmc=4703711 |doi=10.1016/j.ebiom.2015.10.030}}

Like BCL2, BCL3, BCL5, BCL6, BCL7A, and BCL10, it has clinical significance in lymphoma.

Common variations in the BCL9 gene, which is in the distal area, confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder.{{cite journal |vauthors=Li J, Zhou G, Ji W, Feng G, Zhao Q, Liu J, Li T, Li Y, Chen P, Zeng Z, Wang T, Hu Z, Zheng L, Wang Y, Shen Y, He L, Shi Y |display-authors=6 |title=Common variants in the BCL9 gene conferring risk of schizophrenia |journal=Archives of General Psychiatry |volume=68 |issue=3 |pages=232–240 |date=March 2011 |pmid=21383261 |doi=10.1001/archgenpsychiatry.2011.1 |doi-access=free}}

BCL9, together with the paralogue protein BCL9l and PYGO2 also have cytoplasmic functions during tooth development and is particularly important for the formation of enamel. Mice lacking both Pygo1 and Pygo2 or both Bcl9 and Bcl9l develop teeth, a process that requires Wnt/β-catenin transcriptional regulation, but the enamel is structurally disorganized and contains less iron than teeth from control mice. Bcl9, Bcl9l, and Pygo2 are present in the cytoplasm of ameloblasts, the cells that secrete enamel proteins, and colocalize in these cells with amelogenin, the main component of enamel, encoded by the AMELX gene, which has been already implicated as a causative factor of Amelogenesis Imperfecta in humans. Bcl9 interacts with amelogenin and proteins involved in exocytosis and vesicular trafficking, suggesting that these proteins function in the trafficking or secretion of enamel proteins. Therefore, Bcl9, Bcl9l, and Pygo2 have cytoplasmic functions distinct from their roles as transcriptional cofactors downstream of Wnt signaling.{{cite journal |vauthors=Cantù C, Pagella P, Shajiei TD, Zimmerli D, Valenta T, Hausmann G, Basler K, Mitsiadis TA |display-authors=6 |title=A cytoplasmic role of Wnt/β-catenin transcriptional cofactors Bcl9, Bcl9l, and Pygopus in tooth enamel formation |journal=Science Signaling |volume=10 |issue=465 |pages=eaah4598 |date=February 2017 |pmid=28174279 |doi=10.1126/scisignal.aah4598 |s2cid=6845295 |url=http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-145418}} This new discovery might improve our understanding for the treatment of human caries.{{cite news |url=http://www.news-medical.net/news/20170207/Mutated-genes-lead-to-tooth-enamel-defects-that-increase-risk-of-caries.aspx |title=Mutated genes lead to tooth enamel defects that increase risk of caries |date=2017-02-07 |newspaper=News-Medical.net |access-date=2017-02-08}}

• 1q21.1 deletion syndrome
• 1q21.1 duplication syndrome

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• {{cite journal |vauthors=Busson-Le Coniat M, Salomon-Nguyen F, Dastugue N, Maarek O, Lafage-Pochitaloff M, Mozziconacci MJ, Baranger L, Brizard F, Radford I, Jeanpierre M, Bernard OA, Berger R |display-authors=6 |title=Fluorescence in situ hybridization analysis of chromosome 1 abnormalities in hematopoietic disorders: rearrangements of DNA satellite II and new recurrent translocations |journal=Leukemia |volume=13 |issue=12 |pages=1975–1981 |date=December 1999 |pmid=10602418 |doi=10.1038/sj/leu/2401587 |doi-access=}}
• {{cite journal |vauthors=Kramps T, Peter O, Brunner E, Nellen D, Froesch B, Chatterjee S, Murone M, Züllig S, Basler K |display-authors=6 |title=Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex |journal=Cell |volume=109 |issue=1 |pages=47–60 |date=April 2002 |pmid=11955446 |doi=10.1016/S0092-8674(02)00679-7 |s2cid=16720801 |doi-access=free}}
• {{cite journal |vauthors=Knoll A, Dvorák J, Rohrer GA, Cepica S |title=Linkage and cytogenetic mapping of the BCL9 gene to porcine chromosome 4 |journal=Animal Genetics |volume=33 |issue=2 |pages=162–163 |date=April 2002 |pmid=12047235 |doi=10.1046/j.1365-2052.2002.0831e.x}}
• {{cite journal |vauthors=Townsley FM, Thompson B, Bienz M |title=Pygopus residues required for its binding to Legless are critical for transcription and development |journal=The Journal of Biological Chemistry |volume=279 |issue=7 |pages=5177–5183 |date=February 2004 |pmid=14612447 |doi=10.1074/jbc.M309722200 |doi-access=free}}
• {{cite journal |vauthors=Hoffmans R, Basler K |title=Identification and in vivo role of the Armadillo-Legless interaction |journal=Development |volume=131 |issue=17 |pages=4393–4400 |date=September 2004 |pmid=15294866 |doi=10.1242/dev.01296 |doi-access=free}}
• {{cite journal |vauthors=Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP |display-authors=6 |title=Large-scale characterization of HeLa cell nuclear phosphoproteins |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=101 |issue=33 |pages=12130–12135 |date=August 2004 |pmid=15302935 |pmc=514446 |doi=10.1073/pnas.0404720101 |doi-access=free |bibcode=2004PNAS..10112130B}}
• {{cite journal |vauthors=Sampietro J, Dahlberg CL, Cho US, Hinds TR, Kimelman D, Xu W |title=Crystal structure of a beta-catenin/BCL9/Tcf4 complex |journal=Molecular Cell |volume=24 |issue=2 |pages=293–300 |date=October 2006 |pmid=17052462 |doi=10.1016/j.molcel.2006.09.001 |doi-access=free}}
• {{cite journal |vauthors=Hoffmans R, Basler K |title=BCL9-2 binds Arm/beta-catenin in a Tyr142-independent manner and requires Pygopus for its function in Wg/Wnt signaling |journal=Mechanisms of Development |volume=124 |issue=1 |pages=59–67 |date=January 2007 |pmid=17113272 |doi=10.1016/j.mod.2006.09.006 |s2cid=17642255 |doi-access=free}}

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• {{UCSC gene info|BCL9}}
• {{PDBe-KB2|O00512|B-cell CLL/lymphoma 9 protein}}

{{PDB Gallery|geneid=607}}