Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood

Abstract

TEL is a new member of the ETS family of transcription factors which is rearranged in a number of hematologic malignancies with translocations involving chromosome band 12p13. In some cases, both TEL alleles are affected, resulting in loss of wild-type TEL function in the leukemic cells. In addition, 5% of children with acute lymphoblastic leukemia (ALL) have 12p12-p13 deletions, suggesting that a tumor suppressor gene resides on 12p. These observations led us to consider whether TEL loss of function may contribute to the pathogenesis of ALL. In this report we show that the TEL gene maps between the polymorphic markers D12S89 and D12S98, and we use these flanking markers to screen paired diagnosis and remission samples from 81 children with ALL for loss of heterozygosity (LOH) at the TEL gene locus. Fifteen percent of informative patients showed TEL LOH which was not evident on cytogenetic analysis. Detailed examination of patients with LOH at this locus showed that the critically deleted region included two candidate tumor suppressor genes: TEL and KIP1, the gene encoding the cyclin- dependent kinase inhibitor p27. These studies show that LOH at the TEL locus is a frequent finding in childhood ALL.

Microsatellite instability and other molecular abnormalities in childhood acute lymphoblastic leukaemia

“…These loci and chromosomal locations (in parentheses) were: Mfd27 (5q), APC (5q), LPL (8p), 635/636 (15q), Mdf41 (17p) and DCC (18q) (Loeb, 1994;Uchida et al, 1994;Mironov et al, 1994;Egawa et al, 1995;Tasaka et al, 1996;Kaneko et al, 1995). In addition, 79 microsatellite markers in the regions that show alterations in ALL were also analysed (Takeuchi et al, 1995a, b;Takeuchi et al, 1996;Raimondi, 1993;Stegmaier et al, 1995). These markers included three on 6p, 25 on 6q, 18 on 9p, four on 9q, eight on 11q, 16 on 12p, and five on 12q.…”

Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15ink4B/p16ink4 gene inactivation in childhood acute lymphoblastic leukaemia

“…Malignant cells from 74 children with ALL were screened for genetic alterations of chromosome arms 6q, 9p, 12p and 13q, detectable by analysis of LOH by dinucleotide repeat (microsatellite) analysis. The 12p markers were chosen because of their genetic proximity to the TEL gene (Stegmaier et al, 1995). The 6q markers were chosen from the chromosomal region previously described to be frequently deleted in childhood ALL (Hayashi et al, 1990) and the 13q markers map to both the Rb tumour suppressor locus and an adjacent region frequently deleted in various lymphoid neoplasms (Liu et al, 1995).…”

“…Studies on the long arm of chromosome 13 including the Rb gene and adjacent telomeric chromosomal regions on 13q have revealed that deletions of this region are relatively common (Liu et al, 1995). It has been shown recently that translocations involving the TEL gene on 12p are also frequent and often lead to LOH for 12p markers through loss of the remaining TEL allele (Shurtleff et al, 1995;Stegmaier et al, 1995). Furthermore, cytogenetic studies have revealed deletion of material from the long arm of chromosome 6 in approximately 10% of ALL clones (Hayashi et al, 1990).…”

Outcome and lineage involvement in t(12;21) childhood acute lymphoblastic leukaemia

“…Finally, the extremely poor outcome of two out of the 11 (18·2%) TEL/AML1 positive patients of our series, in the absence of other classic poor-risk factors, contrasts with the fact that the t(12;21) translocation could represent an independent good prognostic indicator (Shurtleff et al, 1995) and is in keeping with recent data suggesting that this translocation may be present in a similar proportion of relapsed cases of childhood ALLs (Chambost et al, 1996). In order to investigate whether the more malignant disease present in these two cases could possibly be related to the presence of additional genetic lesions beside the TEL/AML1 rearrangement, we looked for the presence of a deletion of the TEL allele on the homologous chromosome, which had been previously reported to occur in a quite high proportion of the TEL/AML1 rearranged cases Romana et al, 1995a, b;Stegmaier et al, 1995). We found deletion of the contralateral allele in one out of six cases tested at diagnosis, but no association between LOH and fatal outcome was found, as the only case showing a clear LOH is alive and in continuous remission.…”

“…Loss of heterozygosity (LOH) analysis of the TEL gene. In six TEL/AML1 positive cases, DNA was also available and LOH analysis was performed by PCR amplification of the D12S89 microsatellite sequence, as reported elsewhere (Stegmaier et al, 1995).…”