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

Abstract

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.

Lymphoblastic transformation of follicular lymphoma: a clinicopathologic and molecular analysis of 7 patients

“…It has been described in the literature under various names, including acute lymphoblastic leukemia, precursor B cell blast crisis, atypical Burkitt lymphoma, and Burkitt-like lymphoma, with approximately 13 cases described in the literature [4,7,[10][11][12][13][14][15]23,24]. All cases are characterized by loss of follicular architecture and acquisition of blastoid morphology and of TdT, partial or complete loss of immunoglobulin light chain, loss of Bcl6, and increased proliferation index.…”

Burkitt Lymphoma Arising From Lymphoplasmacytic Lymphoma Following Acquisition of MYC Translocation and Loss of the ETV6 Tumor Suppressor Gene

“…The light chain switch has been reported in various transformed lymphomas. 14 The mechanism of alteration in our case is uncertain because of lack of materials to conduct further molecular experiments.…”

Double-hit B-cell lymphomas

“…48,100,101 Intriguingly, at least some of these cases do not really represent a neoplasm of precursor B cells but B cells that may have reexpressed TdT, because they have accumulated somatic hypermutations, a hallmark of GC B cells. 102,103 Whatever the nature of these exceptional cases may be, many DH lymphoblastic cases in the Mitelman database 8 are incompletely documented without data on expression of TdT or CD34.…”