Premalignant cell dynamics in indolent B-cell malignancies

Follicular lymphoma and chronic lymphocytic leukemia (CLL) are indolent B-cell malignancies characterized by a long preclinical phase and frequent relapses once treatment is initiated. The present review gathers recent findings on the occurrence, relevance, and dynamics of premalignant cells in the development of follicular lymphoma and CLL.

The frequency of circulating cells bearing the follicular lymphoma hallmark translocation t(14;18) in healthy persons is correlated to the risk of developing follicular lymphoma later in life. Chronic B-cell receptor stimulation induces cyclic re-entries of BCL2 B cells into germinal centers that propagate clonal evolution and early follicular lymphoma progression. The lymph node microenvironment is a key activation/proliferation niche for malignant cells in CLL, also active in its preclinical antecedent monoclonal B-cell lymphocytosis.

Considering recent studies of premalignant cells in both diseases and of their putative normal cell counterparts, we propose different models of premalignant evolution for the two pathologies. Before overt follicular lymphoma, t(14;18) B cells exploit the dynamics of memory B cells to re-enter multiple times into local or distant germinal centers, gather activation/proliferation signals, and gain additional mutations to progress to malignant lymphoma. In monoclonal B-cell lymphocytosis, CLL-like activated/memory B cells follow cycles of germinal center-independent activation/proliferation in lymph node. Finally, we discuss the next level genetic and functional analyses that should result in a better understanding of the origins and mechanisms of frequent relapses in follicular lymphoma and CLL.