Altered Apoptosis Pathways in Mantle Cell Lymphoma

Abstract

Mantle cell lymphoma (MCL) is an aggressive subentity of non-Hodgkin lymphoma (NHL), responds poorly to therapy, is resistant to current therapeutic strategies and has the shortest survival of all lymphoma entities. The blastoid variant of mantle cell lymphoma (MCL-BV) has an even worse clinical outcome. The mechanisms of neoplastic transformation from normal mantle cells and the relationship to the rare blastoid variant are poorly understood. BCL2 is overexpressed in indolent B-cell NHL including MCL. In addition, other proteins of the BCL-family are overexpressed in MCL like BCLX, whereas the expression of BAX and BAK was not elevated in MCL. BCL2 independent apoptotic pathways are altered in MCL. CD40, which can mediate B-cell survival, is overexpressed in MCL. Furthermore, the expression of FAS which is known to be pro-apoptotic is markedly decreased favoring the CD40 mediated cell survival pathway in these cells. Besides overexpression of cyclin D1, the cyclin dependent kinases (CDK2 and CDK4) are highly expressed in MCL resulting in the phosphorylation of RB1, E2F release, and the cell cycle progression. The new technique of gene expression analysis by microarrays promotes more insight into the pathogenesis of MCL and discovery of altered cell signaling pathways, and the ability to predict subgroups of patients with different risk and probability of response to treatment.