Inactivation of the P16INK4/MTS1 gene by a chromosome translocation t(9;14)(p21-22;q11) in an acute lymphoblastic leukemia of B-cell type.
We have reported previously a preliminary study of a t(9;14)(p21-22; q11) in B-cell acute lymphoblastic leukemia. This translocation had rearranged the TCRA/D locus on chromosome band 14q11 and the locus encoding the tumor suppressor gene P16INK4/MTS1 (P16) on band 9p21 (D. Duro et al., Oncogene, 11: 21-29, 1995). In the present report, the breakpoints were precisely localized on each chromosome partner. On the 14q- derivative, the sequence derived from chromosome 9 was interrupted at 1.0 kb upstream of the first exon of P16, close to a consensus recombination heptamer, CACTGTG. In addition, the chromosome 14 breakpoint was localized at the end of the TCRD2 (delta 2) segment, and 22 residues with unknown origin were present at the translocation junction. On the 9p+ derivative, chromosome 9 sequences were in continuity with those displaced onto chromosome 14, and the 14q11 breakpoint was located within TCRJA29 segment. These features are consistent with aberrant activity of the TCR gene recombinase complex. Although all three coding exons of P16 were displaced onto the chromosome 14q-derivative, no P16 transcript was detected in the leukemic cells. Because the region spanning the P16 exon 1 was not inactivated by methylation and because the other P16 allele was deleted, the implication is that the chromosome breakpoint was likely to disrupt regulatory elements involved in the normal expression of the gene. As a whole, then, our results show that translocations affecting band 9p21 can participate to the inactivation of P16, thus justifying a systematic survey of translocations of the 9p21 band in acute lymphoblastic leukemia.
Duro
D
D
Unité 301 INSERM, Centre National de la Recherche Scientifique, Institute of Molecular Genetics, Paris, France.
Bernard
O
O
Della Valle
V
V
Leblanc
T
T
Berger
R
R
Larsen
C J
CJ
D001483:Base Sequence; D001853:Bone Marrow / Q000473:pathology; D002051:Burkitt Lymphoma / Q000097:blood / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002874:Chromosome Mapping; D002883:Chromosomes, Human, Pair 14; D002899:Chromosomes, Human, Pair 9; D016384:Consensus Sequence; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D015342:DNA Probes; D005091:Exons; D016147:Genes, Tumor Suppressor; D006801:Humans; D007621:Karyotyping; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping; D014178:Translocation, Genetic
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D017931:DNA Primers; D015342:DNA Probes