Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1996-05-28
1999-03-16
Kemmerer, Elizabeth C.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 724, 436813, 536 2431, 935 19, 935 21, 935 78, C12Q 168, C07H 2104
Patent
active
058828583
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Throughout this application various references are referred to within parenthesis. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of each Experimental Detail Section.
Non-random chromosomal abnormalities are found in up to 90% of patients with non-Hodgkin's lymphoma (NHL) and have been shown to play an important role in lymphomagenesis by activating proto-oncogenes (1). Some of these translocations, which are associated with specific histologic subsets of NHL, have been characterized at the molecular level. In the t(8;14), t(8;22), and t(2;8) translocations associated with Burkitt Lymphoma, L.sub.3 -type acute lymphoblastic leukemia and AIDS-associated non-Hodgkin lymphoma (NHL), a known proto-oncogene, c-myc, was found juxtaposed to the immunoglobulin (Ig) loci (2,3). In the t(14;18) translocation, which is implicated in follicular-type NHL, molecular analysis of the sequences linked to the Ig locus led to the identification of a novel proto-oncogene, bcl-2 (4-6). The t(11;14) (q13;q32), mainly associated with "mantle zone" lymphoma, appears to involve the juxtaposition of the Ig heavy-chain locus with the bcl-1 locus, the site of the candidate proto-oncogene PRAD-1/cyclin D1 (7,8). These well characterized chromosome translocations are associated, however, with only a fraction of NHL cases, while a number of other recurrent translocations remain to be characterized for their genetic components.
One important example of such cytogenetic abnormalities is represented by various alterations affecting band 3q27. This region is involved in translocations with various chromosomal sites including, but not limited, to those carrying the Ig heavy- (14q32) or light- (2p12, 22q11) chain loci (9,10). Overall, 3q27 breakpoints are detectable in 7-12% of B-cell NHL cases by cytogenetic analysis, with t(3;22) (q27;q11) being the most frequent type detectable in 4-5% of NHL (9). The clinicopathologic relevance of 3q27 breakpoints is underscored by its consistent association with diffuse-type NHL, a frequent and clinical aggressive subtype for which no specific molecular lesion has yet been identified (9).
The recurrence of 3q27 breakpoints in NHL has prompted a search for the corresponding proto-oncogene. This invention discloses the cloning of clustered 3q27 breakpoints from two NHL cases carrying t(3;14) (q27;q32) translocations and the identification of genomic rearrangements within the same breakpoint region in additional NHL cases carrying translocations involving 3q27. Within the same region, a transcriptional unit has been identified, which represents the candidate proto-oncogene (bcl-6) associated with 3q27 translocations in B-NHL.
SUMMARY OF THE INVENTION
This invention provides an isolated vertebrate nucleic acid molecule of bcl-6 locus. This invention provides an isolated vertebrate DNA molecule of bcl-6 locus. This invention provides an isolated vertebrate cDNA molecule of bcl-6. This invention provides an isolated genomic DNA molecule of bcl-6. This invention provides an isolated vertebrate RNA molecule of bcl-6. This invention provides an isolated human nucleic acid molecule of bcl-6 locus.
In addition, this invention provides a nucleic acid molecule comprising a nucleic acid molecule of at least 15 nucleotides capable of specifically hybridizing with a sequence included within the sequence of the nucleic acid molecule of bcl-6.
In addition, this invention provides an isolated vertebrate DNA molecule of bcl-6 operatively linked to a promoter of RNA transcription. This invention provides a vector which comprises the isolated vertebrate DNA molecule of bcl-6.
In addition, this invention provides the above vector, wherein the isolated nucleic acid molecule is linked to a plasmid.
In addition, this invention provides a host vector system for the production of a polyp
REFERENCES:
patent: 5015568 (1991-05-01), Tsujimoto et al.
patent: 5149628 (1992-09-01), Croce et al.
Sambrook et al. Molecular Cloning: A Laboratory Manual Second Edition vols. 1, 2 and 3. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York, U.S.A. Nov., 1989.
Otsuki T; Yano T; Clark H M; Bastard C; Kerckaert J P; Jaffe E S; Raffeld M. Analysis of LAZ3 (BCL-6) status in B-cell non-Hodgkins's lymphomas: results of rearrangement and gene expression studies and a mutational analysis of coding region sequences. B May 1995.
Baron, B.W., et al. (1993) "Identification of the gene associated with the recurring chromosomal translocations t(3;14) (q27;q32) and t(3;22) (q27;q11) in B-cell lymphomas." Proc. Natl. Acad. Sci. 90: 5262-5266.
Bastard, C. et al. (1992) "Translocations involving band 3q27 and Ig gene regions in non-Hodgkin's lymphoma." Blood 79: 2527-2531.
Cleary, M.L. and J. Sklar (1985) "Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18." Proc. Natl. Acad. Sci. 82:7439-7443.
Kerckaert, J.-P., et al. (1993) "LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas." Nature Genetics 5:66-70 (Exhibit B).
Offit, K., et al., (1989) "A novel translocation associated with diffuse non-Hodgkin's lymphoma." Blood 74:1876-1879.
Rosati, M., et al. (1991) "Members of the zinc finger protein gene family sharing a conserved N-terminal module." Nuc. Acids Res. 19:5661-5667.
Van Cong, N., et al. (1989) "The human homologues of Fim1,Fim2/c-Fms, and Fim3, three retoviral integration regions involved in mouse myeloblastic leukemias, are respectively located on chromosomes 6p23, 5q33, and 3q27." Human Genet 81:257-263.
Ye, B.H., et al. (1993) "Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma." Cancer Research 53:2732-2735.
Ye, B.H. et al. (1993) "Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma." Science 262:747-750 (Exhibit C).
Chaganti Raju S. K.
Dalla-Favera Riccardo
Kemmerer Elizabeth C.
Romeo David S.
Sloan-Kettering Institute for Cancer Research
The Trustees of Columbia University in the City of New York
White John P.
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