IgG-switched CLL has a distinct immunogenetic signature from the common MD variant: ontogenetic implications.
OBJECTIVE
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.


METHODS
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.
Authors' Affiliations: Hematology Department and HCT Unit, G. Papanicolaou Hospital; Institute of Applied Biosciences, Centre for Research & Technology Hellas, Thessaloniki, Greece; Division of Molecular Oncology, San Raffaele Scientific Institute, Milan, Italy; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Hematology Department, Nikea General Hospital, Piraeus, Greece; and Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
Anna
A
Vardi
Andreas
A
Agathangelidis
Lesley-Ann
LA
Sutton
Maria
M
Chatzouli
Lydia
L
Scarfò
Larry
L
Mansouri
Vassiliki
V
Douka
Achilles
A
Anagnostopoulos
Nikos
N
Darzentas
Richard
R
Rosenquist
Paolo
P
Ghia
Chrysoula
C
Belessi
Kostas
K
Stamatopoulos
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte; D006801:Humans; D007125:Immunogenetics; D007072:Immunoglobulin D / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011947:Receptors, Antigen, B-Cell / Q000145:classification / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin
D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell