Common clonal origin of chronic lymphocytic leukemia and high-grade lymphoma of Richter's syndrome

Abstract

Patients with B-cell chronic lymphocytic leukemia (CLL) infrequently may develop high-grade B-cell lymphoma, or Richter's syndrome lymphoma (RS lymphoma). Such lymphomas differ from the original leukemia in both histology and clinical behavior. Studies seeking to define the clonal relationship between the cells of the two malignancies in any one patient have yielded conflicting reports. We examined the clonal relationship between the early and late neoplastic cells of a patient who underwent Richter's transformation. In contrast to the original leukemia cells, the secondary high-grade lymphoma was CD5-. However, both the leukemia cells and the evolved RS lymphoma expressed surface IgM lambda reactive with Lc1, a murine monoclonal antibody specific for a supratypic cross-reactive idiotype encoded by a subset of human Ig variable region genes of the VH4 subgroup. Nucleic acid sequence analyses of the heavy and light chain variable region genes expressed by both leukemia and lymphoma cells show that the CD5- B-cell lymphoma constitutes a clonal expansion of mutant cells derived from the original CD5+ B-cell leukemia. Moreover, certain sets of somatic mutations distinguish the Ig variable region genes used by RS lymphoma from those expressed by the CLL B cells. This is the first study to establish the clonal relationship between CLL and RS lymphoma through primary structural analyses of the expressed Ig genes.

Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome

“…However, in our series, the frequency of IGHV4-39 in RS (4/17; 23AE5%) was significantly higher than in non-transforming CLL (4/161; 2AE4%) (P = 0AE003). This difference was confirmed also when comparing IGHV4-39 prevalence in RS patients from this and previous studies (11/72; 15AE2%; this study and Cherepakhin et al, 1993;Matolcsy et al, 1994;Aoki et al, 1995;Ghiotto et al, 2004;Timár et al, 2004;Reiniger et al, 2006;Smit et al, 2006;Mao et al, 2007) versus prevalence in an expanded database of clinically unselected CLL from our institution (12/427; 2AE8%) (P < 0AE001). The potential relevance of IGHV4-39 in RS transformation is further supported by evidence of stereotyped B-cell receptors in a subset of RS cases using IGHV4-39.…”

Large‐cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome

“…IgM (=ÿIgD), CD5 , CD10 ÿ and CD23 ÿ , with one exception which, however, does not exclude the MC origin of the tumours. The loss of CD5, observed in this case, may be due to CD5 down-regulation, as reported in large-cell lymphomas developing in chronic lymphocytic leukaemia (Richter's syndrome) (Sun et al, 1990;Schots et al, 1991;Cherepakhin et al, 1993;Matolcsy et al, 1994), and was counterbalanced by a strong reactivity with CD43, a feature that usually parallels CD5 reactivity (Contos et al, 1992;Treasure et al, 1992). Of equal importance, the neoplastic growth of large cells was associated with a distinct meshwork of follicular dendritic cells, as typical of MCL.…”

B-cell lymphoma associated with chronic lymphatic leukaemia: two cases with contrasting aggressive and indolent behaviour

“…Sequence analysis of this region has produced proof that high-grade lymphoma can arise from the CLL clone in Richter's syndrome. 16,17 However, some cases show diversity of sequence strongly suggestive of independent clonal origin. 17 We report here molecular analyses of the CDR3 region of skin and blood samples from two patients with CLL who developed cutaneous B-cell lymphoma (CBCL) and demonstrated diverse clinical outcomes.…”