Molecular mechanisms of lymphomagenesis through transcriptional disregulation by chromosome translocation.

Chromosome translation plays an important role for lymphomagenesis. Transcriptional disregulation type of chromosome translocation involves a majority of B-cell lymphoma. These include BCL1/cyclin D1 translocation in mantle cell lymphoma, BCL2 in follicular lymphoma and BCL6 in diffuse large B-cell lymphoma. It is known that the transcriptional disregulation type causes aberrant gene expression at the stages where those genes are down-regulated in normal counterpart cells. Normal B-cells at mantle zone stage down-regulate the expression of BCL1 gene and become resting in cell cycle. However, BCL1 expression from translocated allele with immunoglobulin gene is not down-regulated at the mantle zone stage, preventing cells from entering in resting state, and puts cells in cell cycle, leading to development of mantle cell lymphoma. BCL2 expression from altered allele also keeps its expression at the germinal center stage where normal counterpart cells down-regulate BCL2 expression, and makes cells to resist apoptosis, leading to development of follicular lymphoma. The same scenario can apply to diffuse large B-cell lymphoma with BCL6 translocation; i.e. aberrant BCL6 expression at the post germinal center stage takes place where normal counterpart cells down-regulate BCL6 expression. Although a strong association of specific translocations with specific disease types is found, these translocations by themselves are not sufficient for malignant transformation. The factors other than chromosome translocations will be discussed.