Immunoglobulin genes in multiple myeloma: expressed and non-expressed repertoires, heavy and light chain pairings and somatic mutation patterns in a series of 101 cases.
OBJECTIVE
The available data on the immunoglobulin gene (IG) repertoire in multiple myeloma (MM) derive mainly from heavy chains; considerably less is known about light chains. We assessed in parallel IGH and IGK/IGL rearrangements in 101 MM patients so as to gain insight into: (i) IG repertoires; (ii) antigen impact; (iii) the role of receptor editing.


METHODS
Bone marrow aspirates were collected from all cases. IGHV-(D)-J and IGLV-J rearrangements were amplified by reverse transcriptase polymerase chain reaction (PCR). In all cases, IGKV-J rearrangements were analyzed in parallel on cDNA/genomic DNA. IGKV-KDE and IGKJ-C-INTRON-KDE were also amplified by DNA-PCR. RT-PCR products were directly sequenced.


RESULTS
IGHV3 genes predominated; the IGHV4-34 gene was used in only one case. Five IGKV and five IGLV genes accounted for the majority of in-frame, transcribed IGKV-J or IGLV-J rearrangements. Taking IGKV-J, IGKV-KDE and IGKJ-C-INTRON-KDE rearrangements together, biallelic IGK locus rearrangements were detected in 22/43 k-MM cases. In l-MM, 36/42 cases had at least one rearranged IGK allele; 8/19 IGKV-J rearrangements in l-MM were in-frame. All in-frame, transcribed IGH/IGK/IGL sequences were mutated; parallel heavy/light chain analysis demonstrated a comparable impact of somatic hypermutation.


CONCLUSIONS
Biases in IG repertoire did not seem disease-related but followed a similar pattern to that of the normal repertoire. The under-representation of the IGHV4-34 gene provides an explanation for the paucity of autoimmune phenomena in MM. Somatic mutation patterns indicate the complementary role of MM IGH/IGK/IGL sequences in antigen recognition. Finally, the frequent inactivation of productive IGKV-J joints by secondary rearrangements in MM suggests active receptor editing.
Hadzidimitriou
Anastasia
A
Hematology Department and Hematopoietic Cell Transplantation Unit, G. Papanicolaou Hospital, Thessalonik, Greece. stavstam@otenet.gr
Stamatopoulos
Kostas
K
Belessi
Chrysoula
C
Lalayianni
Chrysavgi
C
Stavroyianni
Niki
N
Smilevska
Tatjana
T
Hatzi
Katerina
K
Laoutaris
Nikolaos
N
Anagnostopoulos
Achilles
A
Kollia
Panagoula
P
Fassas
Athanasios
A
D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D030561:Databases, Nucleic Acid; D015321:Gene Rearrangement / Q000276:immunology; D005803:Genes, Immunoglobulin; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007147:Immunoglobulin Light Chains / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology*; D009154:Mutation; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains