Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia.
Recognition of biased immunoglobulin variable (IgV) gene usage in B-cell chronic lymphocytic leukemia (B-CLL) may yield insight into leukemogenesis and may help to refine prognostic categories. We explored Ig variable heavy (VH) and light (VL) chain gene usage in highly stable and indolent B-CLL (n=25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated VH3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; P<0.01), including mutated cases (6/432; 1.39%; P<0.01) and was exceptional among indolent (1/230, 0.435%; P<0.01), and aggressive B-cell lymphomas (0/105; P<0.01). Three of six VH3-72 B-CLL cases utilized the same VL Vkappa4-1 gene. Two V(H)3-72 B-CLL cases had highly homologous VH complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized Vkappa4-1 genes with homologous IgVL CDR3s. An identical threonine to isoleucine change at codon 84 of V(H)3-72 framework region 3 (FR3) recurred in four cases of highly stable VH3-72 B-CLL. This mutation is expected to cause a conformational change of FR3 proximal to CDR3 that might critically affect high-affinity antigen binding. B-cell receptors encoded by VH3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.
Capello
D
D
Hematology Unit, Department of Medical Sciences & IRCAD, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Guarini
A
A
Berra
E
E
Mauro
F R
FR
Rossi
D
D
Ghia
E
E
Cerri
M
M
Logan
J
J
Foà
R
R
Gaidano
G
G
D000595:Amino Acid Sequence; D001483:Base Sequence; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics; D015321:Gene Rearrangement; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000737:chemistry / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D011379:Prognosis; D011487:Protein Conformation; D011947:Receptors, Antigen, B-Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D011947:Receptors, Antigen, B-Cell