OLIGOMERIZATION OF THE ABL TYROSINE KINASE BY THE ETS PROTEIN TEL IN HUMAN LEUKEMIA

TEL is a member of the Ets family of transcription factors which are f requently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and charact erization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusi on confers growth factor-independent growth to the murine hematopoieti c cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated a nd localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL k inase-inactivating mutation is not constitutively phosphorylated and i s nontransforming but retains cytoskeletal localization. However, cons titutive phosphorylation, cytoskeletal localization, and transformatio n are all dependent upon a highly conserved region of TEL termed the h elix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligom ers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the T EL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligom erization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.