Blood, 1 October 2000, Vol. 96, No. 7, pp. 2550-2556
NEOPLASIA
Isotype switch variants reveal clonally related
subpopulations in diffuse large B-cell lymphoma
Christian H. Ottensmeier and
Freda K. Stevenson
From the Molecular Immunology Group, Tenovus
Laboratory, Southampton University Hospitals, Southampton,
England.
Primary diffuse large B-cell lymphomas (DLBCLs) are aggressive
tumors accounting for approximately 40% of B-cell malignancies. The
immunoglobulin (Ig) variable region genes have undergone rearrangement and are commonly somatically mutated. The majority show intraclonal variation which indicates that somatic mutation has continued after
transformation. Typically, cells of DLBCLs express Ig of a
single isotype, but there may be accompanying cells that express alternative isotypes. To probe the status of the isotype switch process
in DLBCL, 4 cases of tumor-derived constant region transcripts of all isotypes were investigated. Following the identification of the
VDJ sequences, the presence of the major isotype expected from
immunohistochemical analysis was confirmed at the RNA level. Another
3-4 alternative isotypes were revealed in all cases, some of which
could also be detected by immunohistochemistry. All cases were
somatically mutated with an intraclonal variation. In 2 cases there
were clearly distinct patterns of somatic mutation between isotypes,
which was consistent with independent evolution of the tumor
subpopulations. There was apparent clustering of mutational patterns
into either an IgMD/IgG3/IgA set or an IgG1/IgA set, indicating that
the switch to IgA can occur by different routes. Alternative isotype
expression is evident in DLBCL at both the RNA and protein levels. The
pattern of mutation indicates that switching is occurring in
subpopulations of the tumor after malignant transformation. The
findings support the concept that isotype switch events may be a
feature of DLBCL.
