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 iso type-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 hu man MM. These isotype-switch variants were not found in an in vitro stroma- independent variant of the 5T33MM line. However, when this 5T33MM(vitro) li ne was injected into young syngeneic mice; isotype-switch variants appeared thereafter in the isolated tumour cells. These isotype-switch variants cou ld only originate from the MM-IgG expressing cell since IgG subclones from the 5T33MM(vitro) line again gave rise to isotype-switch variants. The appe arance 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 C mu region is deleted from the CIS-chromosome. Th is study demonstrates that isotype-switch variants originate from the major tumour clone suggesting no role for the MM-ISM expressing cell as a pre-sw itch 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.