The goal of this application is molecular genetic analysis of low grade non-Hodgkin's lymphoma (LG-NHL) in order to understand the molecular pathology of this clinically important but poorly understood subset of NHL. The candidate genes deregulated in six specific chromosome rearrangements will be targeted for analysis. These comprise of three primary translocations [t(1;17)(p36;q21), t(6;14)(p21;q32), and t(9;14)(p13;q32)] which are associated with a subset of small lymphocytic lymphoma (SM-LYML) with plasmacytoid/prolymphocytoid (PL) features and two rearrangements [t(1;14)(q21;q32) AND INV(14)(Q24Q32)] which are associated with a subset of small lymphocytic lymphoma (SM-LYML) with plasmacytoid/prolymphocytoid (PL) features and two rearrangements [t(1;14)(q21;q32) and inv(14)(q24q32)] which are associated with progression of follicular lymphoma (FL) with the t(14;18)(q32;q21) translocation. Our overall hypothesis is that isolation and characterization of normal and deregulated functions of genes which participate in specific rearrangements in LG-NHL will contribute to an understanding of its biology and clinical behavior.
The Specific Aims for this application are as follows: (1). To isolate and characterize the candidate genes at 6p21 and 9p13 which participate in t(6;14)(p21;q32) and t(9;14)(p13;q32) translocations seen in SM-LYML,PL. IGH gene probes will be utilized in Southern blotting and library screening to identify non01G rearranged fragments from target genes as was successfully done by us previously. (2). To isolate and characterize the candidate genes at 1p36 and 17q21 sites in the t(1;17)(q36;q21) translocation seen in SM-LYML,PL. The translocation junction will be identified first in YACS and then in cosmids by fluorescence in situ hybridization (FISH). The candidate genes affected by the translocation will be cloned by chromosome walking and exon detection techniques. (3) To isolate, by way of IGH-gene-associated rearrangements (see Aim 1 above), and characterize candidate genes at 1q21 and 14q24 involved in t(1;14)(q21;q32) and inv(14)(q24q32), respectively, which occur as additional chromosome abnormalities in FL with t(14;18)(q32;q21). (4) To isolate and characterize, using probes derived from the candidate 9p13 locus, junctions of recurring translocations involving chromosomal sites other than 14q32. These studies can be expected to identify additional novel deregulated genes of significance to lymphoma, as well as shed light on the molecular basis of instability at this locus. As the novel genes are isolated, their genomic organization and the encoded products (mRNA, cDNA, protein) will be characterized. The regulation of their normal expression and the mechanism(s) of deregulation will be determined. Their biological activity will be assayed with two endpoints: in vitro transformation following transfection and over expression and in vivo tumorigenesis following introduction in mice as transgenes. Specific antibodies will be developed to screen tumors for expression and to perform clinical correlation analyses.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Mammalian Genetics Study Section (MGN)
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Jacobson, James W
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Sloan-Kettering Institute for Cancer Research
New York
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