Bcl-1/IgH Gene Rearrangement In Mantle Cell Lymphoma And Its Potential Molecular Mechanism

[Objective]: Mantle cell lymphoma (MCL) is a distinct entity of non-Hodgkin's lymphoma arising from a subset of naive CD5 + B cells localized in primary follicles or in the mantle zone of secondary follicles with characteristic pathologic, immunophenotypic and molecular genetic features. At present, little is known about it. Current definitive diagnosis of MCL is primary based on morphologic characteristics with a typical growth pattern and a specific immunophenotype spectrum. Nevertheless the distinction from other NHL entities, for example, atypical CLL or follicular lymphoma, and the classification of MCL into existing schemes are sometimes difficult. Diagnosing MCL correctly remains problematical. The specific cytogenetics hallmark of mantle cell lymphoma is (11;14) (q13;q32) chromosonial translocation that juxtaposes the bcl-1 gene on chromosome 1 1q13 with the J 5 region of the IgLI (imniunoglobulin heavy chain) locus on chromosome 1 3q32, and its molecular counterpart is bcl-l/IgH gene rearrangement. Several groups have demonstrated that PCR techniques are capable of detecting bcl-1/IgH gene rearrangement. However, these studies have been performed on genomic DNA obtained from fresh-frozen material, only very few data are available by using formalin-fixed, paraffin-embedded tissues as sample source, and it is not in good agreement as compared with data from fresh-frozen tissues. In fact, formalin-fixed samples are commonly available clinically. Therefore, The aim of the first part in this study is to design a set of primers not only suitable for the fresh-frozen material, but also suitable for the formalin-fixed samples, to detect the bcl-l/IgH gene rearrangement in MCL. Abnormal gene arrangement caused by chromosomal translocations has been associated with specific histologic types of non-Hodgkin's Iymphomas and play an important role in the development of the neoplasm. Mantle cell lymphoma is characterized by t(l l;14)(q13;q32) chromosomal translocatton and its molecular counterpart bcl-1/Igl-I gene arrangement. But up to now, the knowledge concerning the molecular mechanism responsible for this rearrangement is very limited. It was generally thought the t(14;18) (q32;q21) translocation occurred at the initial phase of IgH gene arrangement when the diversity (D) to joining (JH) gene segments assembly, which is caused by an error of recombinase during early B-cell differentiation. Therefore, we suppose that the bcl-1/IgH rearrangement is also mediated by the mechanism V-D-J recombination similar to the t( 14; 18) during the early stage of pre-B cell ontogeny. So, in the second part of this study, we characterized the 6 ~Th~A* bcl-1/IgH junction DNA sequences by direct PCR sequencing from the diagnostic MCL lymph node sample, focusing on the breakpoint in the MTC region, JH involved in the rearrangement, and possible homologous sequence to recognized D segments and recombination motifs. The recognition of more accurate mechanism of the bcl-l/lgH gene rearrangement will improve our understanding of clinical evolution of the disease, and help us to develop new therapeutic strategies. [Methods]: A total of 28 clearly diagnosed with MCL on morphologic criteria for MCL, were selected for MCL. 28 samples were fresh-frozen lymph nodes...