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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1087-1093
Molecular features responsible for the absence of immunoglobulin
heavy chain protein synthesis in an IgH subgroup of
multiple myeloma
Tomasz Szczepa ski,
Mars B. van 't Veer,
Ingrid L. M. Wolvers-Tettero,
Anton W. Langerak, and
Jacques J. M. van Dongen
From the Department of Immunology and Department of Hematology,
Erasmus University Rotterdam/University Hospital Rotterdam, Rotterdam,
The Netherlands; Department of Paediatric Haematology and Chemotherapy,
Silesian Medical Academy, Zabrze, Poland.
This study involved 12 patients with multiple myeloma (MM), in whom
malignant plasma cells did not contain immunoglobulin heavy chain (IgH)
protein chains. Southern blot analysis revealed monoallelic
JH gene rearrangements in 10 patients,
biallelic rearrangement in 1 patient, and biallelic deletion of the
JH and Cµ regions in 1 patient.
Heteroduplex polymerase chain reaction analysis enabled the
identification and sequencing of 9 clonal JH
gene rearrangements. Only 4 of the joinings were complete
VH-(D)-JH
rearrangements, including 3 in-frame rearrangements with evidence of
somatic hypermutation. Five rearrangements concerned incomplete
DH-JH joinings, mainly
associated with deletion of the other allele. Curiously, in at least 1 of these 5 cases the second allele seemed to be in germline
configuration, whereas the in-frame V -J gene rearrangements contained somatic mutations. The configuration of
the IGH genes was further investigated by use of
CH probes. In 5 patients the rearrangements in
the JH and CH regions
were not concordant, probably caused by illegitimate IGH class
switch recombination (chromosomal translocations to 14q32.3). These
data indicate that in many IgH MM patients illegitimate
IGH class switch rearrangement or illegitimate deletion of the
functional
VH-(DH)-JH allele are responsible for IgH negativity. For example, the exclusive presence of
DH-JH
rearrangements in combination with mutated IGK genes can only
be explained in terms of normal B-cell development, if the second
(functional) IGH allele is deleted, which was probably the case
in most patients. Therefore, defects at the DNA level are responsible
for the lack of IgH protein production in most IgH MM patients.
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