Anna Johnson

Somatic hypermutation and VH gene usage in mantle cell lymphoma

Abstract:  Mantle cell lymphoma (MCL) is considered to derive from naïve, pregerminal center (GC) CD5+ B‐cells. However, the cell of origin has been questioned in recent studies that showed somatic hypermutations in the immunoglobulin (Ig) variable heavy chain (VH) genes in subsets of MCL. To clarify this issue, we analyzed the IgVH genes for the presence of somatic hypermutations in 51 MCL cases. Twenty percent of the MCL cases displayed somatically mutated VH genes (defined as >2% mutated), whereas 80% showed unmutated VH genes. This finding suggests that MCL is a genetically heterogeneous disease, with the majority of cases originating from unmutated pre‐GC B‐cells and a subset deriving from more mature B‐cells which have been exposed to the GC environment and have undergone somatic hypermutation. A biased VH gene usage has been demonstrated in several B‐cell malignancies; however, this has not yet been investigated in MCL, although VH4‐34 overusage has been indicated by small studies. Interestingly, we found a restricted usage of three individual VH genes in our MCL material; VH4‐34 (22%), VH3‐21 (16%) and VH5‐51 (12%). This novel finding of preferential VH gene usage in half of the MCL cases may suggest an antigen driven process occurring in B‐cells expressing specific VH genes, thus implicating that Ig specificity could be involved in mantle cell lymphoma development.

Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant

Objectives: The aim of the first Nordic mantle cell lymphoma (MCL) protocol was to study the clinical significance of an augmented CHOP induction chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplantation (ASCT) and to examine the prognostic significance of stem cell contamination rates in newly diagnosed patients with MCL.

Association between telomere length and V H gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications

The immunoglobulin VH gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated VH genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated VH genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and VH gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between VH gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 6.3 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months). Furthermore, the Ig gene sequence data revealed that samples with high mutations frequency (>6%) had long telomeres (∼8 kbp). Thus, both the telomere and VH gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction.

Flow cytometric light chain analysis of peripheral blood lymphocytes in patients with non-Hodgkin's lymphoma

Peripheral blood lymphocytes from 96 patients with non-Hodgkins lymphoma were studied, either at primary staging, during treatment or in follow up. The amount of surface immunoglobulin light chain per cell was determined by direct immunofluorescence staining analysed by flow cytometry. Discrepancy between kappa and lambda fluorescence profiles in the sample was considered to indicate the presence of monoclonal cells i.e., circulating lymphoma cells. The results were correlated with routine haematological findings, histopathology of the lymphoma and tumour burden. Using routine haematological methods leukaemic spread was evident in 24% of the patients in our study. Using kappa/lambda distribution analysis evidence of circulating lymphoma cells was found in an additional 27%. As expected, the major diagnostic gain was in the low grade malignant group, where 30% of the patients with normal peripheral blood according to standard procedures showed evidence of circulating lymphoma cells in the kappa/lambda distribution analysis. The corresponding gain in the high grade malignant group was 19%. In patients with active disease but without morphological evidence of leukaemia, 37% showed abnormal kappa/lambda distributions. In patients in complete remission the corresponding figure was 18%. The clinical significance of small numbers of circulating lymphoma cells is not yet understood, but a possible outlook is to use kappa/lambda distribution analysis to increase staging precision and in the early detection of relapse.