The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia

Abstract

A recurrent t(12;21)(p13;q22) has recently been described in human acute lymphoblastic leukemias (ALLs). This translocation fuses TEL and AML1, two genes previously cloned from translocation breakpoints in myeloid leukemias. In addition, allelic loss of the TEL gene can be detected in 15% to 22% of childhood ALLs. In the present study, we have sought allelic deletions of TEL and the presence of the t(12;21) in 50 children with B-lineage ALL, using a combination of microsatellite typing, fluorescent in situ hybridization (FISH), and analysis of the fusion transcripts resulting from the TEL-AML1 gene fusion. Our results indicate that the association between the t(12;21) and the deletion of the nontranslocated allele of TEL is among the most frequent abnormalities observed in B-lineage ALLs. FISH analysis using several cosmid probes showed that, in one patient with a t(12;21) translocation involving TEL, the second allele had an intragenic deletion. This observation points to TEL as the actual target of 12p12–13 deletions in patients that associate a t(12;21) with a deletion. The TEL-AML1 fusion RNA was found in all patients with the t(12;21) whereas the reciprocal AML1-TEL transcript was only found in a subset of patients, suggesting that only the protein product encoded by TEL-AML1 is likely to play a role in leukemogenesis. The observation that, in two patients with the t(12;21), a deletion of TEL was only present in a subclone indicates that this deletion was a secondary event that occurred after the translocation. The frequent occurrence of TEL deletions in patients with t(12;21) suggests that the deletion of the normal TEL allele subsequent to the t(12;21) provides a further proliferative advantage to leukemic cells.

Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study

“…We have previously described deletion of the 5¢ AML1 signal in a study using exon specific probes (Jabbar Al-Obaidi et al, 2002). This is further supported by molecular studies, which showed that the TEL/AML1 fusion RNA was present in all patients with t(12;21), whereas the reciprocal AML1/TEL transcript was found only in a subset of these patients (Raynaud et al, 1996) and by the fact that other significant chromosomal rearrangements are associated with deletions (Kolomietz et al, 2001).…”

Complex chromosomal abnormalities in utero, 5 years before leukaemia*

“…In acute lymphoblastic leukaemia (ALL), the ETV6/AML1 rearrangement is often associated with a deletion of part or all of the second copy of the ETV6 gene (located at 12p13). A high proportion of cases have this deletion, indicating that it could be the event that precipitates the progression to acute leukaemia (Raynaud et al, 1996;Kempski et al, 1999;Douet-Guilbert et al, 2003). A deletion of ETV6 was not seen in the isolated, fusion positive cells identified in normal cord blood samples by fluorescence in situ hybridization (FISH), which supports this hypothesis (Mori et al, 2002).…”

“…ETV6/AML1 fusion, however, appears to need a genetic 'second hit' for pathogenic transformation. Up to 88% of cases that are positive for ETV6/AML1 fusion have been shown to have a deletion of part or all of the second copy of the ETV6 gene at 12p13 (Raynaud et al, 1996;Kempski et al, 1999;Douet-Guilbert et al, 2003). Deletion of ETV6 is therefore an attractive candidate for this 'second hit', deemed to be essential for progression to overt leukaemia.…”

Quantification of TEL–AML1 transcript for minimal residual disease assessment in childhood acute lymphoblastic leukaemia

“…The TEL±AML1:TBP ratio found for patient 12, whose blasts expressed only the TEL (exon 5)±AML1 (exon 3) fusion transcript, was 1´4, which did not differ from ratios found in patients displaying the usual breakpoint (Table II). Leukaemia blasts of patients 7, 11, and 15 showed chromosome 21 trisomy, which often leads to a der(21)t(12;21) duplication (Raynaud et al, 1996). However, no significantly higher TEL±AML1 expression was evidenced in these patients (Table II).…”

“…Although fusion transcripts are present only in 40% of childhood ALL, quantification of chimaeric messengers provides a useful alternative approach for MRD assessment because of its good sensitivity and because of the stability of such markers over time. The TEL±AML1 transcript, which is associated with t(12;21), is particularly interesting because it is found in 25% of childhood B-cell precursor ALL (Romana et al, 1995;Shurtleff et al, 1995;Raynaud et al, 1996;Borkhardt et al, 1997).…”