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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 724-732
Detection of t(4;14)(p16.3;q32) Chromosomal Translocation in Multiple
Myeloma by Double-Color Fluorescent In Situ Hybridization
Palma Finelli,
Sonia Fabris,
Savina Zagano,
Luca Baldini,
Daniela Intini,
Lucia Nobili,
Luigia Lombardi,
Anna Teresa Maiolo, and
Antonino Neri
From the Laboratorio di Ematologia Sperimentale e Genetica
Molecolare, Servizio di Ematologia, Istituto di Scienze Mediche,
Università degli Studi di Milano, Ospedale Maggiore IRCCS, Milan,
Italy.
Chromosomal translocations involving the immunoglobulin heavy chain
(IGH) locus at chromosome 14q32 represent a common mechanism of
oncogene activation in lymphoid malignancies. In multiple myeloma (MM),
variable chromosome partners have been identified by conventional cytogenetics, including the 11q13, 8q24, 18q21, and 6p21 loci. We and
others have recently reported a novel, karyotypically undetectable chromosomal translocation t(4;14)(p16.3;q32) in MM-derived cell lines,
as well as in primary tumors. The 4p16.3 breakpoints are relatively
scattered and located less than 100 kb centromeric of the fibroblast
growth factor receptor 3 (FGFR3) gene or within the recently
identified WHSC1 gene, both of which are apparently deregulated
by the translocation. To assess the frequency of the t(4;14)(p16.3;q32)
translocation in MM, we performed a double-color fluorescent in situ
hybridization (FISH) analysis of interphase nuclei with differently
labeled probes specific for the IGH locus (a pool of plasmid
clones specific for the IGH constant regions) or 4p16.3 (yeast
artificial chromosome (YAC) 764-H1 spanning the region involved in
breakpoints). Thirty MM patients, the MM-derived cell lines KMS-11 and
OPM2, and six normal controls were examined. The identification of a
t(4;14) translocation, evaluated as the presence of a der(14)
chromosome, was based on the colocalization of signals specific for the
two probes; a cutoff value of 15% (mean + 3 standard deviation
[SD]) derived from the interphase FISH of the normal
controls (range, 5% to 11%; mean ± SD, 8.16 ± 2.2) was used for
the quantification analysis. In interphase FISH, five patients (one in
clinical stage I, two in stage II, one in stage III, and a plasma cell
leukemia) were found to be positive ( 15%). FISH metaphases with
split or colocalized signals were detected in only two of the
translocated cases and confirmed the pattern found in the interphase
nuclei. Furthermore, in three of the five cases with the translocation,
FISH analysis with the IGH joining probe (JH) showed the
presence of the reciprocal product of the translocation [der(4)
chromosome]. Overall, our study indicates that the t(4;14)(p16.3;q32)
chromosomal translocation is a recurrent event in MM tumors and may
contribute towards the detection of this lesion and our understanding
of its pathogenetic and clinical implications in MM.
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