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Blood, 15 August 2001, Vol. 98, No. 4, pp. 1174-1181
NEOPLASIA
Tumor cells of hairy cell leukemia express multiple clonally
related immunoglobulin isotypes via RNA splicing
Francesco Forconi,
Surinder
S. Sahota,
Donatella Raspadori,
Christopher I. Mockridge,
Francesco Lauria, and
Freda K. Stevenson
From Molecular Immunology Group, Tenovus Laboratory,
Southampton University Hospitals, Southampton, United Kingdom; and
Cattedra e U.O. di Ematologia, Ospedale A. Sclavo, Universita'
degli Studi di Siena, Siena, Italy.
Hairy cell leukemia (HCL) derives from a mature B cell and
expresses markers associated with activation. Analysis of
immunoglobulin variable region genes has revealed somatic
mutation in most cases, consistent with an origin from a cell that has
encountered the germinal center. One unusual feature of hairy cells
(HCs) is the frequent expression of multiple immunoglobulin
heavy chain isotypes, with dominance of immunoglobulin (Ig)-G3, but
only a single light chain type. The origin and clonal relationship of
these isotype variants have been unclear. In order to probe the isotype
switching status of HCL, RNA transcripts of
VHDJH- constant region sequences from 5 cases
of typical HCL, all expressing multiple surface immunoglobulin isotypes, were analyzed. Tumor
VHDJH-Cµ sequences were
identified and found to be somatically mutated (range, 1.4% to 6.5%),
with a low level of intraclonal heterogeneity. Additional
immunoglobulin isotypes of identical VHDJH
sequence were also identified, including IgD (5 of 5), IgG3 (5 of 5),
IgG1 (3 of 5), IgG2 (2 of 5), IgA1 (4 of 5), and IgA2 (1 of 5).
Derivation of multiple isotypes from individual cells was demonstrated
by analyzing transcripts in single sorted cells from one patient, with
evidence for coexistence of isotype variants in 10 of 10 cells. These
findings indicate that clonally related multiple isotypes coexist in
single HCs, with individual isotypes presumably generated via RNA
splicing. Production of IgG3 appears common, but IgG1, IgG2, IgA1, and
IgA2 also arise, indicating a continuing influence of a directed
process on the tumor clone. These HCs appear to be arrested at the
point of isotype switch, where RNA processing may precede deletional recombination.
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