Deregulation of PAX-5 by translocation of the Emu enhancer of the IgH locus adjacent to two alternative PAX-5 promoters in a diffuse large-cell lymphoma.

Analyses of the human PAX-5 locus and of the 5' region of the mouse Pax-5 gene revealed that transcription from two distinct promoters results in splicing of two alternative 5' exons to the common coding sequences of exons 2-10. Transcription from the upstream promoter initiates downstream of a TATA box and occurs predominantly in B-lymphocytes, whereas the TATA-less downstream promoter is active in all Pax-5-expressing tissues. The human PAX-5 gene is located on chromosome 9 in region p13, which is involved in t(9;14)(pl3;q32) translocations recurring in small lymphocytic lymphomas of the plasmacytoid subtype and in derived large-cell lymphomas. A previous molecular analysis of a t(9;14) breakpoint from a diffuse large-cell lymphoma (KIS-1) demonstrated that the immunoglobulin heavy-chain (IgH) locus on 14q32 was juxtaposed to chromosome 9p13 sequences of unknown function [Ohno, H., Furukawa, T., Fukuhara, S., Zong, S. Q., Kamesaki, H., Shows, T. B., Le Beau, M. M., McKeithan, T. W., Kawakami, T. & Honjo, T. (1990) Proc. Natl. Acad. Sci. USA 87,628-632]. Here we show that the KIS-1 translocation breakpoint is located 1807 base pairs upstream of exon 1A of PAX-5, thus bringing the potent Emu enhancer of the IgH gene into close proximity of the PAX-5 promoters. These data suggest that deregulation of PAX-5 gene transcription by the t(9;14)(pl3;q32) translocation contributes to the pathogenesis of small lymphocytic lymphomas with plasmacytoid differentiation.

[1]  Prof. Dr. med. Karl Lennert,et al.  Malignant Lymphomas Other than Hodgkin’s Disease , 1978, Handbuch der Speziellen Pathologischen Anatomie und Histologie.

[2]  R. Flavell,et al.  β + Thalassemia: Aberrant splicing results from a single point mutation in an intron , 1981, Cell.

[3]  T. Rabbitts,et al.  Transcription enhancer identified near the human Cμ immunoglobulin heavy chain gene is unavailable to the translocated c-myc gene in a Burkitt lymphoma , 1983, Nature.

[4]  J. Banerji,et al.  A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes , 1983, Cell.

[5]  M. Olson,et al.  Cloning of large segments of exogenous DNA into yeast by means of artificial chromosome vectors. , 1987, Science.

[6]  M. Neuberger,et al.  A second B cell-specific enhancer 3' of the immunoglobulin heavy-chain locus , 1990, Nature.

[7]  M. Kozak.  Structural features in eukaryotic mRNAs that modulate the initiation of translation. , 1991, The Journal of biological chemistry.

[8]  A. Aguzzi,et al.  Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis. , 1992, Genes & development.

[9]  M. Busslinger,et al.  The promoter of the CD19 gene is a target for the B-cell-specific transcription factor BSAP , 1992, Molecular and cellular biology.

[10]  B. Sauer,et al.  A positive selection vector for cloning high molecular weight DNA by the bacteriophage P1 system: improved cloning efficacy. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S. Korsmeyer,et al.  Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. , 1992, Annual review of immunology.

[12]  Pavel Urbánek,et al.  Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9 , 1993, Nature Genetics.

[13]  D. Torney,et al.  Construction and characterization of a YAC library with a low frequency of chimeric clones from flow-sorted human chromosome 9. , 1993, Genomics.

[14]  M. Busslinger,et al.  Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties , 1993, Molecular and cellular biology.

[15]  B. Emanuel,et al.  Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma , 1993, Nature Genetics.

[16]  E. E. Max,et al.  The B cell-specific transcription factor BSAP regulates B cell proliferation , 1994, The Journal of experimental medicine.

[17]  W. Mellado,et al.  BCL-6 and the molecular pathogenesis of B-cell lymphoma. , 1994, Cold Spring Harbor symposia on quantitative biology.

[18]  E. Wagner,et al.  Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5 BSAP , 1994, Cell.

[19]  E T Stuart,et al.  Mammalian Pax genes. , 1994, Annual review of genetics.

[20]  M. Busslinger,et al.  The role of BSAP (Pax-5) in B-cell development. , 1995, Current opinion in genetics & development.

[21]  P. Gruss,et al.  PAX5 expression correlates with increasing malignancy in human astrocytomas. , 1995, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  A. Aguzzi,et al.  Deregulated expression of PAX5 in medulloblastoma. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[23]  M. Busslinger,et al.  Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron , 1995, Molecular and cellular biology.