Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B cell receptor immunoglobulins (BcR IG). Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR IG stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR IG stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. In order to address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29,856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed 'satellites', were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL.

T Cells in Chronic Lymphocytic Leukemia: A Two-Edged Sword

“…This clinical evidence complements immunogenetic evidence that the BcR IG is a key driver in disease ontogeny and evolution. In more detail, the BcR IG gene repertoire is characterized by remarkable restrictions ( 88 ), culminating in BcR IG stereotypy where, at clear odds with serendipity, different clones share (quasi)identical IG ( 4 , 5 , 89 ). Moreover, the molecular characteristics of the clonotypic BcR IG have established prognostic and predictive significance since patients with a significant imprint of somatic hypermutation (SHM) display indolent disease, in contrast to those with few or no SHM who generally follow a more aggressive clinical course ( 90 , 91 ).…”

“…Numerous studies support that the clonotypic B cell receptor immunoglobulin (BcR IG) is critically implicated in disease pathophysiology ( 2 ). Indeed, the intensity of intracellular signaling downstream of the BcR in CLL cells is associated with cell proliferation and disease severity ( 3 ), whereas restrictions in the gene repertoire of the clonotypic BcR IG strongly highlight the role of antigenic triggering in disease pathogenesis ( 4 , 5 ).…”

The Traf2DNxBCL2-tg Mouse Model of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Recapitulates the Biased IGHV Gene Usage, Stereotypy, and Antigen-Specific HCDR3 Selection of Its Human Counterpart

“…Of note is that the average pI of the HCDR3 of UM-CLL/SLL clones from the Traf2DNxBCL2-tg +/+ is significantly more acidic than the average pI of the HCDR3 from the Eµ-TCL-1-tg UM-CLL clones (4.5 ± 1.4 vs. 5.9 ± 1.9) (P=0.02). Identical HCDR3 Are Expressed in Traf2DNxBCL2-tg +/+ CLL/SLL Clones From Distinct Mice A distinctive characteristic of human CLL is the expression of structurally identical or highly similar HCDR3 between unrelated individuals producing structurally similar BCRs (14,15,46). This occurrence is known as HCDR3 stereotypy and points out toward the role of antigens in the clonal selection and pathogenesis of the disease [reviewed in (17,30,47)].…”

“…This occurrence is known as HCDR3 stereotypy and points out toward the role of antigens in the clonal selection and pathogenesis of the disease [reviewed in (17,30,47)]. Stereotyped HCDR3 rearrangements account for 41% of human CLL clones (15). BCR stereotypes are also found in CLL clones from the Eµ-TCL-1-tg (28,31) and from the MDR −/− and miR-15a/16-1 −/− (32) mice, among others.…”

“…In addition, CLL can also be classified according to the expression of stereotyped HCDR3, which are found in a 41% of CLL patients (14,15). Indeed, the remarkable similarity of HCDR3 regions within sets of patients strongly supports the notion that B cell receptor (BCR) recognition of particular antigens is a driving force in clonal selection, expansion and evolution in CLL [reviewed in (16,17)].…”