Myeloma isotype-switch variants in the murine 5T myeloma model: evidence that myeloma IgM and IgA expressing subclones can originate from the IgG expressing tumour.
Isotype-switch variants can easily be detected in a significant proportion of multiple myeloma (MM) patients. The biological significance of these isotype-switch variants remains obscure. Therefore, we studied the appearance of these isotype-switch variants in two murine MM models, 5T2MM and 5T33MM, both of IgG isotype. With a MM-specific PCR assay we could detect isotype-switch variants in the bone marrow of both the 5T2MM and the 5T33MM bearing mice, reflecting again the close resemblance of this mouse model to the human MM. These isotype-switch variants were not found in an in vitro stroma-independent variant of the 5T33MM line. However, when this 5T33MMvitro line was injected into young syngeneic mice, isotype-switch variants appeared thereafter in the isolated tumour cells. These isotype-switch variants could only originate from the MM-IgG expressing cell since IgG subclones from the 5T33MMvitro line again gave rise to isotype-switch variants. The appearance of IgA cells can be explained by down-stream switching of IgG to IgA, while the emergence of IgM cells have to occur via trans-switching to the sister chromatid as the Cmu region is deleted from the CIS-chromosome. This study demonstrates that isotype-switch variants originate from the major tumour clone suggesting no role for the MM-IgM expressing cell as a pre-switch precursor MM cell. The appearance of isotype-switch variants should be considered as a rare but normal event now becoming visible due to the high number of clonal cells present in MM.
Bakkus
M H
MH
Department of Haematology and Immunology, KUL, Leuven, Belgium.
Asosingh
K
K
Vanderkerken
K
K
Thielemans
K
K
Hagemeijer
A
A
De Raeve
H
H
Van Camp
B
B
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D007070:Immunoglobulin A / Q000032:analysis*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000032:analysis*; D007075:Immunoglobulin M / Q000032:analysis*; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology*; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M