The cell surface expression of multiple immunoglobulin heavy chain (IG
H) isotypes, preferentially observed in hairy cell leukemia (HCL), is
incompatible with the deletion model of IGH class switching, and alter
native models involving RNA-splicing have been proposed. To help discr
iminate between these possibilities we have examined the configuration
of the IGH locus by DNA blot in 38 cases of HCL. Deletion of at least
one allele of C mu/C delta was seen in 14 cases (37%). Of 12 cases in
which IgG and/or IgA were expressed, three exhibited biallelic deleti
on of C mu/C delta compatible with deletional class-switching whereas
the remaining 9 cases retained both alleles of C mu/C delta, These dat
a indicate that both DNA deletion and RNA-splicing mechanisms of class
-switching may operate in HCL. In a further 17 cases, other unexpected
abnormalities of the IGH locus mapping to the J(H)-C mu intron in one
of two patterns were observed. First, discordance between JH and C mu
in BamHI DNA digests was found in 12 cases. Similar patterns were obs
erved in only 4/91 cases of B-cell chronic lymphocytic leukemia and 0/
15 of B-cell prolymphocytic leukemia. To preclude chromosomal transloc
ations involving the J(H)-C mu intron, rearrangements of BCL1, BCL2, B
CL3, and MYC were sought in 23 cases but none of the cases showed onco
gene rearrangement to the intron. Second, abnormal-sized C mu fragment
s arising as a consequence of abnormalities of the J(H)-C mu intron we
re detected in HindIII, BgIII, and/or Xbal digests in 10/23 cases. In
5 cases abnormal-sized C mu fragments accompanied discordant J(H)-C mu
fragments in BamHI digests. Similar abnormal C mu fragments were not
seen in 15 cases of B-cell prolymphocytic leukemia as well as 13 contr
ol DNA samples. Overall, abnormalities of the J(H)-C mu intron, a regi
on which includes both S mu and enhancer regions, were seen in 14/23 (
61%) of HCL. The nature and consequences of these aberrations remain t
o be determined but preliminary data from molecular cloning experiment
s suggest at least some represent errors in the process of class-switc
hing.