title: The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice.
abstract: Several patients with clinical features of chronic myeloid leukemia (CML) have fusion of the TEL (ETV6) gene on 12p13 with ABL on 9q34 and express a chimeric Tel-Abl protein that contains the same portion of the Abl tyrosine kinase fused to Tel, an Ets family transcription factor, rather than Bcr. In a murine retroviral bone marrow transduction-transplantation model, a Tel (exon 1-5)-Abl fusion protein induced 2 distinct illnesses: a CML-like myeloproliferative disease very similar to that induced by Bcr-Abl but with increased latency and a novel syndrome characterized by small-bowel myeloid cell infiltration and necrosis, increased circulating endotoxin and tumor necrosis factor alpha levels, and fulminant hepatic and renal failure. Induction of both diseases required the Tel pointed homology oligomerization domain and Abl tyrosine kinase activity. Myeloid cells from mice with both diseases expressed Tel-Abl protein. CML-like disease induced by Tel-Abl and Bcr-Abl was polyclonal and originated from cells with multilineage (myeloid, erythroid, and B- and T-lymphoid) repopulating ability and the capacity to generate day-12 spleen colonies in secondary transplantations. In contrast to findings with Bcr-Abl, however, neither Tel-Abl-induced disease could be adoptively transferred to irradiated secondary recipient syngeneic mice. These results show that Tel-Abl has leukemogenic properties from distinct from those of Bcr-Abl and may act in a different bone marrow progenitor.
authors.affiliation: The Center for Blood Research and Department of Genetics, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115, USA.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Million
authors.forename: Jon
authors.initials: J
authors.lastname: Aster
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002881:Chromosomes, Human, Pair 12; D002899:Chromosomes, Human, Pair 9; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000009:adverse effects / Q000235:genetics; D006801:Humans; D007410:Intestinal Diseases / Q000209:etiology / Q000401:mortality; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000401:mortality / Q000473:pathology*; D009368:Neoplasm Transplantation / Q000009:adverse effects / Q000401:mortality / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000009:adverse effects* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000009:adverse effects* / Q000235:genetics; D015996:Survival Rate; D014161:Transduction, Genetic; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D016044:Fusion Proteins, bcr-abl; D015514:Oncogene Proteins, Fusion; D011505:Protein-Tyrosine Kinases; C426234:TEL-ABL fusion protein, human; D000097764:ETS Translocation Variant 6 Protein