IgG-Switched CLL Has a Distinct Immunogenetic Signature from the Common MD Variant: Ontogenetic Implications

Abstract

Purpose: Immunoglobulin G-switched chronic lymphocytic leukemia (G-CLL) is a rare variant of CLL, whose origin and ontogenetic relationship to the common IgM/IgD (MD-CLL) variant remains undefined. Here, we sought for clues about the ontogeny of G-CLL versus MD-CLL by profiling the relevant IG gene repertoires.Experimental Design: Using purpose-built bioinformatics methods, we performed detailed immunogenetic profiling of a multinational CLL cohort comprising 1,256 cases, of which 1,087 and 169 expressed IG mu/delta and gamma heavy chains, respectively.Results: G-CLL has a highly skewed IG gene repertoire that is distinct from MD-CLL, especially in terms of (i) overuse of the IGHV4-34 and IGHV4-39 genes and (ii) differential somatic hypermutation (SHM) load. Repertoire differences were also found when comparing subgroups with similar SHM status and were mainly attributed to the exclusive representation in G-CLL of two major subsets with quasi-identical (stereotyped) B-cell receptors. These subsets, namely #4 (IGHV4-34/IGKV2-30) and #8 (IGHV4-39/IGKV1(D)-39), were found to display sharply contrasting SHM and clinical behavior.Conclusions: G-CLL exhibits an overall distinct immunogenetic signature from MD-CLL, prompting speculations about distinct ontogenetic derivation and/or immune triggering. The reasons underlying the differential regulation of SHM among G-CLL cases remain to be elucidated. Clin Cancer Res; 20(2); 323-30. Ó2013 AACR.

Immunogenetic Studies of Chronic Lymphocytic Leukemia: Revelations and Speculations about Ontogeny and Clinical Evolution

“…34,35). A recent study of 169 IgG þ CLL cases from our joint cohort revealed that G-CLL exhibits an overall different immunogenetic signature from MD-CLL, even when restricting the comparison to cases with mutated BcR IGs (36). A significant proportion (18%) of this rare subgroup was found to consist of just two major CLL subsets, namely subsets #4 and #8.…”

“…CLL subset #4 (IGHV4-34/IGKV2-30) is considered to bear an inherently autoreactive BcR IG, which is effectively edited by the SHMs in critical positions (19). This may well be in line with the particularly indolent clinical course followed by these patients with CLL (14,36). At the other end of the spectrum, unmutated subset #8 (IGHV4-39/IGKV1(D)-39) carries a BcR IG with a conspicuously broad antigen reactivity profile, perhaps underlying clinical aggressiveness and risk of transformation to high-grade lymphoma (18).…”

Antigen Selection Shapes the T-cell Repertoire in Chronic Lymphocytic Leukemia

“…We also investigated patients with CLL carrying non-subset BcR IG rearrangements, so as not to disregard the possibility of identifying T-cell immunogenetic features that are ubiquitous in CLL, irrespective of the particular IG receptor that is expressed. Our cohort was intentionally biased towards subset #4, where ample evidence suggests ongoing interactions with the selecting antigen (33)(34)(35)(36). For this reason, we also performed longitudinal immunoprofiling of five subset #4 patients, aiming to explore the possibility of clonal drift.…”

Additional trisomies amongst patients with chronic lymphocytic leukemia carrying trisomy 12: the accompanying chromosome makes a difference

“…Considering the low frequency of CLL cases with switched immunoglobulin (IG) in their B-cell receptors (BcR), this finding is highly suggestive of a particular immunopathogenetic process in this patient subgroup. 8 This claim was further supported by the remarkable bias to lambda light chain expression in this particular cytogenetic subgroup [22 of 32 cases (69%) with available data], raising the intriguing possibility that the respective clonogenic progenitors may have been subject to light chain receptor editing. All but one +12+19 CLL case with available information (47 of 48, 98%) carried immunoglobulin heavy variable (IGHV) genes impacted to some degree by somatic hypermutation (SHM), leading to IGHV genes with less than 100% germline identity.…”

“…Panagiotis Baliakas, 1 Anna Puiggros, 2,3 Aliki Xochelli, 1,4 Lesley-Ann Sutton, 1 Florence Nguyen-Khac, 5 Anne Gardiner, 6 Karla Plevova, 7 Eva Minga, 4 Anastasia Hadzidimitriou,4 Renata Walewska, 6 Helen McCarthy, 6 Margarita Ortega, 8 Rosa Collado, 9 Teresa González, 10 Isabel Granada, 11 Elisa Luño, 12 Jana Kotašková, 7 Theodoros Moysiadis, 4 Zadie Davis, 6 Niki Stavroyianni, 13 Achilles Anagnostopoulos, 13 Jonathan C. Strefford, 14 Sarka Pospisilova, 7 Frederic Davi, 5 Anastasia Athanasiadou, 13 Richard Rosenquist, 1 David Oscier, 6 Blanca Espinet, 2,3 Figure 2. Kaplan-Meier curves for overall survival (OS).…”