Lymphoid Malignancies: the dark side of B-cell differentiation

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Abstract
Mature B-cell malignancies are initiated often by errors in immunoglobulin gene variable–diversity–joining region (VDJ) recombination, somatic hypermutation and/or class-switch recombination that lead to chromosomal translocations. Dysregulation of the genes at the translocation breakpoints disrupts B-cell homeostasis by perturbing proliferation, apoptosis and differentiation. Advances in molecular analyses, in particular gene-expression profiling, have increased the precision of diagnosis for lymphoid malignancies. These methods have shown that lymphomas and leukaemias can share gene-expression programmes with their normal cellular counterparts. Molecular profiling has shown that some of the diagnostic categories that are used at present consist of many molecularly distinct diseases that cannot be distinguished morphologically. Antigenic stimulation and selection have crucial roles in the pathogenesis and persistence of some lymphomas and leukaemias. The identification and elimination of an antigenic stimulus can eradicate some tumours. Improved molecular classification and an understanding of the pathogenetic mechanisms that are involved in lymphoid malignancies are providing new molecular targets for therapy.