Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis

Abstract

Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to (i) follow the evolutionary history of the RS clone (ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 3 10 23 vs. 0.13 3 10 -3 ; p 50.002). These data indicate that (i) clonally related RS stems from a cell that is already present within the initial CLL clone and (ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation.The definition of Richter syndrome (RS) encompasses two biologically different conditions: (i) transformation of chronic lymphocytic leukemia (CLL) to clonally related diffuse large B-cell lymphoma (DLBCL) and (ii) development of a DLBCL unrelated to the CLL clone. [1][2][3][4] The role of antigen in promoting CLL transformation to RS is supported by the recent observation of a high prevalence of stereotyped B-cell receptors in CLL transforming to RS, and by the documentation of biased usage of immunoglobulin heavy variable (IGHV) genes, including IGHV4-39. 5,6A common assumption in the context of transformation from indolent to aggressive B-cell malignancy holds that transformation reflects the final stage of evolution of the indolent B-cell clone.7 An alternative scenario, however, might be the divergent evolution of both the indolent and the aggressive phase from a common precursor cell. 7,8 In RS, the precise timing of onset of the RS clone during CLL history is unknown. Also, although antigen stimulation may be important for the growth of indolent B-cell malignancies, it might no longer be required by the subsequent aggressive malignancy.9 With respect to RS, antigen stimulation contributes to CLL predisposition to DLBCL, 6 but it is unclear whether antigen retains any role once that transformation has occurred.

Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia

“…RS is usually manifested by disease transformation into diffuse large B-cell lymphoma, which is often refractory to treatment and carries a poor prognosis. Most RS cases are clonally related to the pre-existing CLL, with TP53 disruption being one of the most frequent underlying genomic alterations2526. Clinically, the diagnosis of RS is often not straightforward and relies on a high index of clinical suspicion and accurate tissue biopsy.…”

Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes

“…The remaining 20% of cases are unrelated to the CLL clone and are considered as second cancer arising in a patient with CLL. [ 52 ] The incidence of RT ranges from 2 to less than 10%. [ 44,53-55 ] The influence of prior treatment especially with purine analogues on the incidence of RT is unclear.…”

Molecular pathogenesis of chronic lymphocytic leukemia

“…Since immunogenetic investigations have shown that the subclone from which RS emerges is already identifiable at CLL diagnosis in most patients who subsequently develop RS (114), deep sequencing studies performed in sequential samples are needed to assess whether traces of the genetic lesions manifestly acquired at RS transformation are already present at CLL diag-nosis. Preliminary evidence suggests that this might be the case, at least in some patients (45).…”