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.

Richter syndrome: a review of clinical, ocular, neurological and other manifestations

“…If the lymphoma arises from different cells, it can be regarded as a secondary cancer arising by chance. In the majority of patients, the large cell lymphoma clone occurs by transformation of the original CLL clone (Tsimberidou & Keating, 2005, 2006; Foresti & Confalonieri, 1984; Traweek et al ,1993; Cherepakhin et al , 1993; Harousseau et al , 1981; Matolcsy et al , 1994) and in fewer cases, as a separate and independent neoplasm (Tsimberidou & Keating, 2005, 2006; Matolcsy et al , 1994; Sun et al , 1990), as shown by characterization of immunoglobulin (Ig) heavy‐chain gene ( IGH ) rearrangements and light‐chain isotype analyses. Richter syndrome may be triggered by viral infections, such as Epstein‐Barr virus (EBV) (Tsimberidou & Keating, 2005; Swords et al , 2007; Tsimberidou & Keating, 2006).…”

Richter syndrome

“…The molecular mechanisms involved in the transformation of CLL to RS are poorly understood. The large cell lymphoma clone occurs either by transformation of the original CLL clone (in the majority of patients)9, 13–23 or as a separate and independent neoplasm,21, 24–29 as shown by characterization of immunoglobulin (Ig) heavy‐chain gene rearrangements and light‐chain isotype analyses. Clonal evolution may be triggered by viral infections, which are common in immunosuppressed patients.…”

Clonal evolution of B cells in transformation from low- to high-grade lymphoma

“…The mechanisms of morphological transformation, clonal evolution and clinical progression in transformed DLBL are poorly understood. Some investigators have indicated the highgrade DLBL cells share the same clonal root with the pre-existing low-grade NHL cells, based on observations that the original and transformed neoplastic B cell populations bear identical Ig V H DJ H gene rearrangements [9][10][11][12]. Others have suggested that the morphological transformation from low-to high-grade B cell lymphoma is often associated with alteration of the expressed Ig genes indicating that clonal diversification is an important event in the emergence of DLBL [13][14][15].…”