We report that fusion of TEL to AML1 is specifically observed in at least 16% of the childhood B-lineage acute lymphoblastic leukemia (ALL) investigated, none of which had been previously identified as harboring t(12;21).
We now demonstrate that a TEL/AML1 chimeric transcript encoded by a cryptic t(12;21) is observed in 22% of pediatric ALL, making it the most common genetic lesion in these patients.
These findings, combined with earlier reports, indicate that TEL/AML1 fusion is the most frequent genetic abnormality in childhood ALL, regardless of race.
These data show the coexistence of multiple genetic defects in childhood B-lineage ALL Cell lines with t(12;21) will facilitate the study of TEL-AML1 and AML1-TEL fusion proteins as well as TEL and CDKN2 gene inactivation in leukemia transformation and progression.
The lack of cases with the TEL-AML1 fusion together with the high frequency of BCR-ABL fusion could largely account for the poorer outcome of adult ALL as compared with childhood ALL.
The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.
The translocation t(12;21)(p13;q22) is a frequent nonrandom rearrangement of B-cell lineage childhood acute lymphoblastic leukemia (ALL) which fuses the TEL and AML1 genes, normally localized to 12p13 and 21q22, respectively.
Using mainly reverse transcriptase-polymerase chain reaction (RT-PCR), the TEL-AML1 chimeric transcript has been observed in 22-27% of pediatric patients with acute lymphoblastic leukemia (ALL), in particular in the early B-lineage ALL subtype, making it the most common genetic lesion in these patients.
More specific to ALL, t(12;21)(p13;q22), resulting in a fusion TEL-AML1, gene has recently been shown to be the most frequent translocation in childhood B-cell lineage ALL (20-30% of cases).
Recently, a new rearrangement involving AML1, the t(12;21), producing the TEL/AML1 hybrid transcript, has been described by molecular analysis as the most recurrent genetic lesion in childhood acute lymphoblastic leukemia (ALL).
To investigate the frequency of the molecular equivalent of the t(12;21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials.
For example, the TEL-AML1 fusion, the most common genetic abnormality in childhood acute lymphoblastic leukemia, was recently shown to be an independent, favorable prognostic factor, suggesting that patients with this abnormality are best treated with conventional antimetabolite-based therapy.
Abnormalities of the short arm of chromosome 12 including loss of heterozygosity (LOH) and TEL/AML-1 fusion resulting from a t(12;21)(p13;q22) translocation are frequently observed in childhood acute lymphoblastic leukemia (ALL).
These findings indicate that absence of the TEL/AML1 fusion transcript partly correlates with the poorer outcome of adult B-cell lineage ALL as compared with childhood ALL and the TEL/AML1 fusion transcript is specific for pediatric B-cell lineage ALL.
Although deletion of ETV6 and t(12;21) were associated in most patients, in eight cases (six B lineage and two T-ALL) LOH was detected at the ETV6 locus without ETV6-AML1 hybrid RNA.
The genes p16 (or MTS1) and TEL/AML1 are now respectively recognized as the most common tumor suppressor and fusion genes in childhood acute lymphoblastic leukemia.
However, using fluorescence in situ hybridization (FISH) and by screening for the TEL/AML1 rearrangement by the polymerase chain reaction (PCR), it has been demonstrated to be the most frequent known structural chromosomal abnormality in childhood acute lymphoblastic leukemia (ALL).
The TEL/AML1 fusion associated with t(12;21)(p13;q22) is the most common gene rearrangement in childhood malignancy, occurring in approximately 25% of pediatric acute lymphoblastic leukemia.
KOR-SA3544 expression over 3% was detected in the majority of TEL/AML1-negative patients with newly diagnosed common or preB ALL (19 of 31) and not in TEL/AML1-positive patients (0 of 18, P < 0.0001).
Fluorescence in situ hybridization (FISH) analysis was applied to detect t(12;21) using two yeast artificial chromosome probes and cosmid probes covering the TEL(ETV6) and the AML1 gene to clarify the incidence of abnormality of t(12;21) in Japanese childhood acute lymphoblastic leukemia (ALL).