Molecular analysis of the T-cell acute lymphoblastic leukemia- associated
t(1;7)(p34;q34) that fuses LCK and TCRB
RC Burnett, MJ Thirman, JD Rowley and MO Diaz
Department of Medicine, University of Chicago, IL.
Previously we had characterized the t(1;7)(p34;q34) translocation from
HSB-2. This translocation fused the beta T-cell receptor gene (TCRB)
constant region and transcriptional enhancer with the type I transcription
unit of the LCK gene on the derivative 1 [der(1)] chromosome. The type II
promoter was translocated to the der(7) chromosome. Regarding the mechanism
of the t(1;7) in HSB-2, we identified an alternating purine-pyrimidine
tract (G-T)17 at the 1p34/LCK breakpoint. Additionally, sequence analysis
of both breakpoint junctions provided data that implicate the V(D)J
recombinase in formation of the t(1;7). A heptamer-nonamer recognition
sequence with a 12-bp spacer was found in the immediate vicinity of the
1p34/LCK breakpoint and, thus, chromosomal breakage at 1p34 may be
explained as resulting from recombinase activity. Because phosphorylation
of Tyr-505 in vivo regulates the tyrosine kinase activity of p56lck we
amplified a region from LCK exon 12 that contains the codon for Tyr-505 and
showed no mutation of this codon in HSB-2 DNA and, therefore, p56lck in
HSB-2 is not activated by mutation of Tyr-505. We have analyzed LCK gene
expression in HSB-2 and SUP-T12 cell lines. RNase protection analysis
identified almost exclusively type I transcripts in HSB-2. An independent
t(1;7) in SUP-T12 also resulted in the juxtaposition of LCK to TCRB. The
breakpoint in SUP-T12 occurred 2 kb 5' of the type II promoter, leaving an
intact LCK gene on the der(1) chromosome. RNase protection analysis
identified both type I and type II LCK transcripts in a 3:1 ratio in
SUP-T12. Factors other than proximity to the TCRB enhancer must affect
promoter utilization in this cell line.
Volume 84,
Issue 4,
pp. 1232-1236,
08/15/1994
Copyright © 1994 by The American Society of Hematology
