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Blood, 1 November 2001, Vol. 98, No. 9, pp. 2762-2770
NEOPLASIA
Isotype-switched immunoglobulin genes with a high load of somatic
hypermutation and lack of ongoing mutational activity are prevalent
in mediastinal B-cell lymphoma
Frank Leithäuser,
Martin Bäuerle,
Minh
Quang Huynh, and
Peter Möller
From the Department of Pathology, University of Ulm,
Germany.
Primary mediastinal B-cell lymphoma (PMBL) is a subentity of
diffuse large B-cell lymphoma with characteristic clinical,
histomorphologic, immunophenotypical, and genetic features. Unlike
other B-cell lymphomas, PMBL has not yet been the subject of
comprehensive molecular studies on the rearranged immunoglobulin (Ig)
gene. Such investigations have proved essential to obtaining
information about the differentiation stage of the lymphomagenic B
cell. In the present study, the clonally rearranged immunoglobulin
heavy-chain gene of 13 PMBL cases is analyzed by polymerase chain
reaction (PCR) in conjunction with cloning and DNA sequencing.
Twelve of 13 rearrangements were potentially functional. All clonally
rearranged immunoglobulin genes bore a high load of somatic mutations
(average, 13.0%), which appeared to be selected for a functional
antibody in the majority of cases. The comparison of cloned PCR
products revealed no evidence of ongoing mutation of the immunoglobulin variable gene. By means of reverse-transcriptase PCR, lymphoma-specific immunoglobulin transcripts were detected in 8 of 13 cases, all of which
were of the postswitched type, whereas immunoglobulin protein
expression was undetectable except for 1 case. A PMBL cell line,
MedB-1, generated from an IgG parental tumor,
constitutively expressed IgG protein in a subset of cells, which was
moderately suppressed by interleukin-4 and up-regulated in the presence
of dexamethasone. PMBL is thus characterized by a heavily mutated,
class-switched immunoglobulin gene without evidence of ongoing
mutational activity. Moreover, our data indirectly suggest that
regulation by extrinsic signals contributes to the immunoglobulin-negative phenotype of PMBL.
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