Relationship between the mutational status of VH genes and pathogenesis of diffuse large B-cell lymphoma in Richter's syndrome

Abstract

Patients with chronic lymphocytic leukemia (CLL) may develop diffuse large B-cell lymphoma (DLBL), also known as Richter's syndrome. Mutational status of immunoglobulin (Ig) heavychain variable region (V H ) genes have prognostic impact in CLL. Patients with mutated V H genes have a stable disease, whereas patients with unmutated V H gene have more aggressive disease. The mutational status of CLLs that transform to DLBL is unknown. To reveal whether Richter's syndrome occurs in CLLs with mutated or unmutated V H genes, we have performed mutational analysis on serial specimens from eight patients. CLL and DLBL tumorclones were identical in five cases and they were different in three cases. Six CLLs expressed unmutated and two cases expressed mutated V H genes. In five of the six unmutated CLLs, the DLBL clones evolved from CLL tumorclones and the V H genes expressed by DLBLs were also unmutated. In one unmutated and two mutated CLLs, the DLBLs expressed mutated V H genes, but in these three cases the DLBL tumorclones developed as independent secondary neoplasm. These results suggest that Richter's syndrome may develop in both mutated or unmutated CLLs, but clonal transformation of CLL to DLBL occur only in the unmutated subgroup of CLL.

Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation

“…In harmony with our prior report, 24 the transforming CLLs, the transformed RTs and PLTs showed unmutated IgV H gene status and the somatic mutation mechanism of the IgV H gene was not activated during the higher-grade transformation of CLLs. These findings suggest that the phisiological process of SHM and ASHM are not necessarily linked together, and ASHM may occur independently of Ig gene mutations.…”

“…Eight cases of CLL (cases [1][2][3][4][5][6][7][8] showed no transformation during the clinical course of the disease, 13 cases (cases 9-21) developed RT and eight cases (cases [22][23][24][25][26][27][28][29] showed PLT. In seven cases of RT (cases 9-15), both CLL and DLBL samples were available for analysis.…”

Richter syndrome: molecular insights and clinical perspectives

“…The disease involves most frequently the lymph nodes, but extra-nodal localizations are also not uncommon, and have been reported in the gastrointestinal tract, skin, liver, tonsil and bone marrow among other sites [3,4,[9][10][11][34][35][36][37][38].…”

“…Cases of RS are known to derive from both IGHV mutated and unmutated CLL, although unmutated CLL are at higher risk and, consequently, unmutated IGHV genes are preponderant in RS clones [3,[9][10][11]. The role of the BCR in determining RS development may also depend upon the characteristics of the IGHV gene utilized by the tumour clone.…”

“…Even when restricting the term RS solely to CLL transformation to DLBCL, the clinical definition of RS is heterogeneous, and encompasses at least two biologically different conditions: (i) transformation of CLL cells to a clonally related DLBCL, that accounts for the majority of cases; (ii) development of a DLBCL that is unrelated to the CLL clone [3,[6][7][8][9][10][11]. In clonally related RS, the pathogenetic link between the CLL and the DLBCL phases is obvious, and is conceivably substantiated by the acquisition of novel molecular lesions at the time of clinicopathologic transformation.…”