The t(8;21) creates a fusion protein between AML-1 and a gene of unknown function, mtg8 (ETO), whereas the t(12;21) fuses the TEL (translocation-ets-leukemia) transcription factor to the N-terminus of AML-1.
These data show that TEL, previously shown to be fused to the platelet-derived growth factor receptor beta in chronic myelomonocytic leukemia, can be implicated in the pathogenesis of leukemia through its fusion to either a receptor tyrosine kinase or a transcription factor.
In addition, the putative loss of wild-type function of CDKN1B and ETV6 could indicate a synergistic effect of both genes in the pathogenesis of this leukemia case.
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.
Rearrangement of the TEL gene distinguishes a large subset of children with favorable-prognosis B-precursor leukemia who cannot be identified by standard prognostic features.
The FISH method clearly demonstrated that all patients with the TEL/AML1 fusion had subpopulations of leukemic cells with deletion of the normal TEL allele, which is significant for understanding the progression of leukemia with t(12;21).
The most plausible explanation for this finding is a single cell origin of the TEL-AML fusion in one fetus in utero, probably as a leukemia-initiating mutation, followed by intraplacental metastasis of clonal progeny to the other twin.
Because many chromosomal alterations in leukemia are associated with distinct cell surface phenotypes, we investigated whether there was an association seen between surface marker expression and the TEL-AML1 rearrangement.
The TEL/AML1 fusion associated with t(12;21)(p13;q22) is the most common gene rearrangement in childhood leukemia, occurring in approximately 25% of pediatric acute lymphoblastic leukemia (ALL), and is associated with a favorable prognosis.
Fluorescence in situ hybridization analysis of leukemia patients with del(12p) further refined the commonly deleted segment to 600 kb between ETV6 and D12S358, which apparently excludes CDKN1B.
Although first described less than four years ago, the TEL/AML1 story is an excellent example of how close collaboration between physicians and molecular biologists is mandatory for achieving general insights into the molecular pathogenesis of leukemia and for further improvements in diagnosis and in monitoring response to chemotherapy.
The E-26 transforming specific (ETS)-related gene TEL, also known as ETV6, is involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma.
These data provide novel insight into the natural history of childhood leukemia and suggest that consequent to a prenatal initiation of a leukemic clone, most probably by TEL-AML fusion itself, the latency of ALL can be both extremely variable and protracted.
Breakpoints in general displayed similar complexity of duplications, deletions, and insertions to other common pediatric leukemia translocations (TEL-AML1, MLL-AF4, PML-RARA, CBFB-MYH11) that we and others have analyzed.
This study provides novel mechanistic insights regarding the chemosensitivity of TEL-AML1(+) ALL cells and provides a cogent explanation for the excellent leukemia-free survival outcome of children with TEL-AML1(+) ALL treated on contemporary chemotherapy programs.