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

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Authors	VARDI A. AGATHANGELIDIS A. SUTTON L.A. CHATZOULI M. SCARFO L. MANSOURI L. DOUKA V. ANAGNOSTOPOULOS A. DARZENTAS Nikos ROSENQUIST R. GHIA P. BELESSI C. STAMATOPOULOS K.
Year of publication	2014
Type	Article in Periodical
Magazine / Source	Clinical Cancer Research
MU Faculty or unit	Central European Institute of Technology
Citation
Web	http://clincancerres.aacrjournals.org/content/20/2/323.long
Doi	http://dx.doi.org/10.1158/1078-0432.CCR-13-1993
Field	Oncology and hematology
Keywords	CHRONIC LYMPHOCYTIC-LEUKEMIA; B-CELL RECEPTOR; GENE MUTATIONAL STATUS; SOMATIC HYPERMUTATION; CLONAL EVOLUTION; UNMUTATED CLL; ANTIGEN; RECOMBINATION; ACTIVATION; EXPRESSION
Description	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. (C) 2013 AACR.
Related projects:	SuPReMMe - Podpora profesního růstu a mezinárodní integrace výzkumných týmů v oblasti molekulární medicíny CEITEC - Central European Institute of Technology