Molecular analysis of light-chain switch and acute lymphoblastic leukemia transformation in two follicular lymphomas: Implications for lymphomagenesis

We observed novel transformations of follicular lymphoma ( FL), first, a switch in immunoglobulin ( Ig) light chain, and second, transformation of FL to acute lymphoblastic leukemia ( ALL). Each set of tumors shared a common clonal origin, as demonstrated by expression of identical, unique CDR IIIH sequences, shared somatic mutations in JH, and identical bcl- 2 translocation breakpoints of microdissected ALL cells. Molecular analysis of lambda V- gene expression demonstrated lambda- bearing cells in the original kappa tumor, while expansion of the lambda subclone at relapse occurred after active immunotherapy targeting the Ig receptor. These exceptional cases are compatible with a more contemporary model of lymphomagenesis in which critical events originate from genetic mechanisms which normally occur in germinal center ( GC) B cells and challenge the current paradigm of parallel generation of subclones from an early, pre- GC precursor. It is also possible that the outgrowth of these variants was a consequence of immunoselection.