t(X;9)(q21;p13) PAX5/DACH2

2014-01-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

Clinics and Pathology

Disease

Acute lymphoblastic leukemia (ALL)

Epidemiology

Only one case to date, a 4-year old boy with a pre-B ALL (Coyaud et al., 2010).

Prognosis

No data.

Genes Involved and Proteins

Gene name
PAX5 (paired box gene 5)
Location
9p13.2
Protein description
391 amino acids; from N-term to C-term, PAX5 contains: a paired domain (aa: 16-142); an octapeptide (aa: 179-186); a partial homeodomain (aa: 228-254); a transactivation domain (aa: 304-359); and an inhibitory domain (aa: 359-391). Lineage-specific transcription factor; recognizes the concensus recognition sequence GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5; activates B-cell specific genes and repress genes involved in other lineage commitments. Activates the surface cell receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007; Medvedovic et al., 2011).
Gene name
DACH2 (dachshund family transcription factor 2)
Location
Xq21.2
Dna rna description
7 splice transcript variants.
Protein description
599 amino acids and shorter forms; from N-term to C-term, contains a Poly-Gly (amino acids (aa) 56-61), a Dachshund domain motif N (aa 69-155), which interact with HDAC3 (histone deacetylase 3, 5q31), NCOR1 (nuclear receptor corepressor 1, 17p11.2), and SIX6 (SIX homeobox 6, 14q23.1), a Poly-Ala (aa 350-353), a Dachshund Domain motif C, which interact with EYA2 (eyes absent homolog 2 (Drosophila), 20q13.1), and a Coiled coil domain (aa 459-554) (Swiss-Prot). DACH2 is a transcriptional repressor of MYOG (myogenin, 1q32.1). PAX3 (paired box gene 3, 2q36.1) and DACH2 positively regulate each other, and support the existence of a PAX3/SIX1/EYA2/LBX1/DACH2 network in regulating the myogenic differentiation program (Mennerich and Braun, 2001; Kardon et al., 2002). Histone deacetylase (HDAC4) activity, imported into the nucleus, suppresses DACH2 gene expression in denervated muscle (Tang and Goldman, 2006; Cohen et al., 2007). DACH2 represses SIX1 (SIX homeobox 1, 14q23.1), and SIX1 overexpression has been described in gliomas. DACH1 (13q22) and DACH2 are required for Müllerian duct development. DACH2 is abundantly expressed in fallopian tubes, and it has been implicated in premature ovarian failure syndrome (Bione et al., 2004; Suzumori et al., 2007). In ovarian cancer, DACH2 is expressed, and a significantly reduced overall survival was found for tumours expressing high levels of DACH2 in the subgroup of serous carcinoma, but not in other subgroups (Nodin et al., 2012).

Result of the Chromosomal Anomaly

Description

Fusion of PAX5 exon 5 to DACH2 exon 3.
Atlas Image
PAX5/DACH2 fusion protein.

Description

587 amino acids. The predicted fusion protein contains the DNA binding paired domain of PAX5 (the 201 N-term aa) and the DACHbox-C of DACH2 (the 386 C-term aa).

Highly cited references

Pubmed IDYearTitleCitations
244351672014Functional heterogeneity of PAX5 chimeras reveals insight for leukemia development.13

Bibliography

Pubmed IDLast YearTitleAuthors
154591722004Mutation analysis of two candidate genes for premature ovarian failure, DACH2 and POF1B.Bione S et al
174404522007Pax5: the guardian of B cell identity and function.Cobaleda C et al
178732802007The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming.Cohen TJ et al
201601642010Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study.Coyaud E et al
150040082004Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene.Fuxa M et al
152585792004B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5.Johnson K et al
121124642002Pax3 and Dach2 positive regulation in the developing somite.Kardon G et al
219709552011Pax5: a master regulator of B cell development and leukemogenesis.Medvedovic J et al
117429942001Activation of myogenesis by the homeobox gene Lbx1 requires cell proliferation.Mennerich D et al
222844332012Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer.Nodin B et al
173055372007Candidate genes for premature ovarian failure.Suzumori N et al
170750712006Activity-dependent gene regulation in skeletal muscle is mediated by a histone deacetylase (HDAC)-Dach2-myogenin signal transduction cascade.Tang H et al
166801442006Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes.Zhang Z et al

Summary

Fusion gene

PAX5/DACH2 PAX5 (9p13.2) DACH2 (Xq21.2) M t(X;9)(q21;p13)

Citation

Jean-Loup Huret

t(X;9)(q21;p13) PAX5/DACH2

Atlas Genet Cytogenet Oncol Haematol. 2014-01-01

Online version: http://atlasgeneticsoncology.org/haematological/1595/t(x;9)(q21;p13)

External Links