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Molecular Cloning of Translocation t(1;14)(q21;q32) Defines a Novel
Gene (BCL9) at Chromosome 1q21
T.G. Willis,
I.R. Zalcberg,
L.J.A. Coignet,
I. Wlodarska,
M. Stul,
D.M. Jadayel,
C. Bastard,
J.G. Treleaven,
D. Catovsky,
M.L.M. Silva, and
M.J.S. Dyer
From the Academic Department of Haematology and Cytogenetics,
Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, UK;
the Centro de Transplante de Médula Óssea, Instituto
Nacional do Cancer, Rio de Janeiro, Brazil; the Centre for Human
Genetics and Flanders Institute of Biotechnology, University of Leuven,
Leuven, Belgium; and the Department of Cytogenetics, Centre
Régional de Transfusion Sanguine et de Génétique
Humaine, Bois Guillaume, France.
Abnormalities of chromosome 1q21 are common in B-cell malignancies
and have been associated with a poor response to therapy. The nature of
the involved gene(s) on chromosome 1q21 remains unknown. A cell line
(CEMO-1) has recently been established from a patient with
precursor-B-cell acute lymphoblastic leukemia (ALL), which exhibited a t(1;14)(q21;q32). To identify the gene involved in
this translocation, we have cloned both rearranged IGHJ alleles using long-distance inverse polymerase chain reaction (LDI-PCR). Two
IGHJ fragments were amplified from CEMO-1 DNA and sequenced. One allele showed novel sequences upstream of JH5 with no
homology to either IGH or any other sequences on the databases.
Using a single-copy Xho I fragment immediately 5 of
JH5, PAC clones were isolated and mapped to chromosome
1q21 on normal metaphases by fluorescence in situ hybridization
(FISH), confirming that this allele represented the
t(1;14)(q21;q32) breakpoint. Sequence analysis of the 1q21 Xho
I fragment showed identity with an expressed sequence tag
(EST), and this probe was therefore used to probe Northern blots. Two transcripts of 6.3 kb and 4.2 kb expressed at low level in
mRNA from all tissues were detected: a third transcript of 1.6 kb was
expressed only in thymus, spleen, and small intestine. Full-length
BCL9 cDNA clones were obtained from a normal human fetal brain
cDNA library supplemented by 5 and 3 RACE. Sequence analysis predicted a protein of 1394 amino acids containing 18% proline, 11% glycine, 11% serine, and 6% methionine, but no
recognizable protein motifs or significant homologies to any other
known proteins. The CEMO-1 1q21 breakpoint fell within the 3 UTR
of the BCL9 gene. Low-level expression of BCL9 was
detected in Epstein-Barr virus-transformed normal B cells by Northern
blot; in contrast, abundant BCL9 expression was observed in
CEMO-1, indicating that deregulated expression of this gene was one
pathological consequence of the translocation. Screening of a panel of
39 B-cell malignancies with 1q abnormalities by Southern blot showed
one additional case with a breakpoint in the 3 UTR of
BCL9, indicating that this was a recurrent breakpoint. FISH
analysis using an 850-kb YAC spanning BCL9 identified a further
case with t(1;22)(q21;q11) causing juxtaposition of BCL9 to the
IG locus. Other breakpoints were heterogeneous, falling both
centromeric (10 cases) and telomeric (10 cases) of the BCL9
gene. These data suggest that BCL9 may be the target of
translocation in some B-cell malignancies with abnormalities of 1q21
and that deregulated BCL9 expression may be important in their
pathogenesis.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 1873-1881
© 1998 by The American Society of Hematology.
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