HEMATOPOIETIC TRANSFORMATION BY THE TEL ABL ONCOGENE/

Rare, novel forms of activated ABL kinase, the result of a fusion betw een TEL (or ETV6, a member of the ETS transcription factor family), an d the non-receptor tyrosine kinase ABL, have been identified. We have analysed the TEL/ABL fusion protein (type A) cloned from an acute lymp hoblastic leukaemia patient, In contrast to a second TEL/ABL fusion (t ype B) identified in two cases of myeloid leukaemia, the portion of TE L contained in the type A TEL/ABL fusion was smaller and did not conta in a potential Grb2 binding site, The type A TEL/ABL cDNA we used in t his study encoded a 155 kD protein with elevated tyrosine kinase activ ity and was responsible for the phosphorylation of a number of protein s in vivo. Its expression in factor-dependent murine haemopoietic prec ursor cells efficiently converted these cells to factor independence f or both survival and growth. These cells continued to express high lev els of myc mRNA after growth factor depletion. We also demonstrated th at type A TEL/ABL self-associated in stably expressing haemopoietic ce lls. Although the TEL portion of the TEL/ABL fusion protein has no seq uence similarity to that of BCR in the BCR/ABL protein, all forms of t hese fusion proteins contain a structure implicated in oligomerization . Our results support the conclusion that the protein interaction doma in of BCR and TEL, but not the Grb2 binding site, are the important fu nctional components in the activation of ABL kinase in haemopoietic di sease.