ABSTRACT
ETS variant gene 6 (ETV6)/translocation, ETS, leukemia (TEL)-involving chromosomal translocations are frequently observed in various hematologic neoplasms. We describe here a novel ETV6-involving translocation, t(12;13)(p13;q14), found in the case of acute lymphoblastic leukemia, in which ETV6 fused with a previously unknown gene, named Twelve-thirteen Translocation Leukemia gene (TTL), at 13q14. TTL was weakly but ubiquitously expressed in normal human tissues as detected by reverse transcribed-PCR. Three TTL splicing forms were identified, TTL-T from a human testis cDNA library, with an open-reading frame of 402 bp encoding 133 amino acids (aa), and TTL-B1 and -B2 from a human brain cDNA library. These proteins have no homology to known proteins. In leukemic cells from the patient, both reciprocal fusion transcripts, ETV6/TTL and TTL/ETV6, were expressed. The predominant fusion transcript, TTL/ETV6-1, encodes a predicted 530 aa fusion protein containing 89 aa of the N-terminal TTL fusing to the helix-loop-helix domain and ETS-binding domain of ETV6. 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.
Subject(s)
Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 13 , DNA-Binding Proteins/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Repressor Proteins/genetics , Translocation, Genetic , Alternative Splicing , Amino Acid Sequence , Base Sequence , Blotting, Southern , Brain , Cloning, Molecular , DNA Primers/chemistry , DNA-Binding Proteins/metabolism , Gene Library , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Middle Aged , Molecular Sequence Data , Oncogene Proteins, Fusion/metabolism , Protein Isoforms , Proto-Oncogene Proteins c-ets , RNA, Neoplasm/blood , RNA, Neoplasm/genetics , RNA, Neoplasm/isolation & purification , Reverse Transcriptase Polymerase Chain Reaction , Testis , ETS Translocation Variant 6 ProteinABSTRACT
We previously identified and cloned a neurite outgrowth promoting protein, Neurocrescin (NC), from the extract of the chick denervated leg muscles. In this study, we explored the active region of NC for neurite outgrowth. Using the deletion mutants of NC, we tested their neurite outgrowth activity in the cultured telencephalic neurons of E5 chick embryos. We found three regions which independently had significant neurite outgrowth activity comparable with that of the extract of the chick denervated leg muscles. These regions were not homologous to any well-known active sites such as the laminin active region, IKVAV. In parallel, searching the endogenous deletion mutants of NC in the rat brain, we cloned a mutant in which the region including the larger part of one of the three active regions was deleted. The neurite outgrowth activity of the mutant was significantly lower than that of normal NC. These results suggest the physiological significance of these active regions.
