Gene expression profiling provided evidence that leukemia in twins harbours the same subtype-typical feature as TEL-AML1-positive leukemia in singletons suggesting that the leukemogenesis model might also be applicable generally.
Additionally, the ETV6-RUNX1 fusion was found to encode putative neoepitopes in a high proportion (69.6%) of the pediatric leukemia harboring this fusion.
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.
We infer that MN1-TEL is a hematopoietic oncogene that stimulates the growth of hematopoietic cells, but depends on secondary mutations to cause leukemia in mice.
MN1TEL, a leukemia-related fusion protein containing parts of the MN1 and TEL (ETV6) genes, is capable of stimulating the IGFBP5 promoter but is unable to cooperate with RA in Hep3B cells.
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 frequent chromosomal changes in subgroups divided according to WHO classification independent of treatment protocol and leukemia subtype were hyperdiploidy in 36 patients (with ≥50 chromosomes in 23 patients, with 47-49 chromosomes 13 patients) followed by translocation t(12;21) with ETV6/RUNX1 fusion detected by FISH in 18 (22%) patients.
Although the function of TTL is yet to be elucidated, our findings will provide another insight into the molecular pathogenesis of leukemia having ETV6-involving translocations.
Together, these data suggest that, unlike most leukemia-associated chromosomal rearrangements, the important consequence of the t(7;12) is likely not the generation of a novel fusion transcript, but instead the inactivation of TEL and/or a gene at 7q36.
As few <i>ETV6-RUNX1</i> carriers develop precursor B-cell acute lymphocytic leukemia (pB-ALL), the underlying genetic basis for development of full-blown leukemia remains to be identified, but the appearance of leukemia cases in time-space clusters keeps infection as a potential causal factor.
The modification of this translocation may lead to reducing effects of the fusion gene's damaging and the dosage compensation related to ETV6 and RUNX1 genes and subsequently reduce the effects of leukemia.
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 low frequency of the TEL/AML1 transcript that is found in developing countries, such as Brazil, may be due to the low incidence of leukemia; this would support Greaves' hypothesis.
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.
We show here for the first time that LPXN is a fusion partner of ETV6 and present evidence indicating that ETV6-LPXN plays a crucial role in leukemia progression through enhancing the response to G-CSF and CXCL12.