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Heterogeneous chromosomal aberrations generate 3' truncations of the
NFKB2/lyt-10 gene in lymphoid malignancies
A Migliazza, L Lombardi, M Rocchi, D Trecca, CC Chang, R Antonacci, NS Fracchiolla, P Ciana, AT Maiolo and A Neri
Laboratorio di Ematologia Sperimentale e Genetica Molecolare, Istituto di
Scienze Mediche, Universita di Milano, Ospedale Maggiore IRCCS, Italy.
The NFKB2(lyt-10) gene codes for a protein that is a member of the NK-
kappa B/rel family of transcription factors containing a DNA-binding rel
domain and a carboxy-terminal ankyrin-like domain. The NFKB2 gene
represents a candidate proto-oncogene, since it has been found to be
involved in a chromosomal translocation t(10;14)(q24;q32) in one case of
B-cell lymphoma and in gene rearrangements in various types of lymphoid
malignancies. To elucidate the structural and functional consequences of
NFKB2 rearrangements, we report the molecular characterization of three
novel rearranged NFKB2 genes in lymphoid tumors. In one case of multiple
myeloma (MM), cloning and sequencing analysis of reciprocal breakpoint
sites showed that they occurred within intron 15 of the NFKB2 gene and led
to the complete deletion of the 3' portion of the gene coding for the
ankyrin domain. Fluorescent in situ hybridization (FISH) analysis showed
that the novel regions involved in the NFKB2 rearrangement originated from
chromosome 7q34, thus implying the occurrence of a t(7;10)(q34;q24)
reciprocal chromosomal translocation. In one case of T-cell cutaneous
lymphoma (CTCL) and in one of B-cell chronic lymphocytic leukemia (B-CLL),
NFKB2 rearrangements occurred, respectively, within exons 18 and 20 of the
gene and involved recombinations with distinct regions of chromosome 10q24.
Molecular analysis suggested that these rearrangements may occur as a
consequence of small internal chromosomal deletions. In both of these
cases, the rearrangements led to specific carboxy-terminal truncations of
NFKB2 generating abnormal transcripts that coded for proteins lacking
portions of the ankyrin domain. These proteins localize in the nucleus,
suggesting their constitutive activation in vivo. Overall, our results
indicate that NFKB2 rearrangements in lymphoid neoplasia may occur by
heterogeneous mechanisms, including internal chromosomal deletion or
chromosomal translocation. The common consequence of these rearrangements
appears to be the deletion of 3' sequences of NFKB2 leading to the
production of carboxy-truncated constitutively nuclear proteins that may be
involved in tumorigenesis.
Volume 84,
Issue 11,
pp. 3850-3860,
12/01/1994
Copyright © 1994 by The American Society of Hematology
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