Cloning of B-Cell Neoplasia associated Translocation Breakpoints

B-cell neoplasias include a group of malignancies which share a common target tissue, lymphoid cells, and are characterized by distinct histologic, immunologic and genetic features as well as their variable clinical presentation and course. The majority (~ 95%) of Non-Hodgkin`s Lymphomas (NHL) derive from the B-cell lineage and, in particular, from mature B-cells, which express cellsurface immunoglobulin (Ig) and B-cell-associated markers and have undergone rearrangement of their immunoglobulin (Ig) heavy- (IgH) and light- (IgL) chain genes. The generation of a functional Ig receptor plays a key role not only in the normal maturation of lymphocytes but also in the molecular pathogenesis of B-cell neoplasia. The most significant pathway to initiation of unregulated proliferation of B-cells is through the activation of genes by chromosomal translocation involving the site of the target gene and the IgH or IgL genes whereby the transcriptional regulatory sequences of the target gene are replaced or otherwise brought under the control of Ig gene promotor-enhancer sequences. Well characterized examples of these chromosomal aberrations are translocations t(8;14)(q24;q32) and variant 8q24 translocations, t(14;18)(q32;q21), t(11;14)(q13;q32), which are characteristic for Burkitt`s lymphoma, follicular lymphoma, and mantle cell lymphoma, respectively. These translocations led to the discovery of the oncogenes c-MYC, BCL-2 and BCL-1, respectively, which are activated by juxtaposition to Ig regulatory elements on chromosomal band 14q32. However, a considerable number of Ig-gene associated translocations has not been investigated at the molecular level, indicating the existence of novel gene(s) relevant in the pathogenesis of B-cell neoplasia. Recently, by using a new molecular cytogenetic technique, spectral karyotyping (SKY), a novel recurring translocation t(12;14)(q24;q32) was described in two multiple myeloma cell lines. A B-CLL patient from our hospital presented with similar translocation t(12;14)(q23;q32). Several other reports provide evidence for the existence of genes relevant to lymphomagenesis on this particular chromosomal region. The goal of this study is the molecular cloning of the chromosomal breakpoints of these translocations and the identification and characterisation of the involved gene(s).