The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways

Inappropriate activation of Abl family kinases plays a crucial role in diff erent human leukaemias, In addition to the well known oncoproteins p190Bcr- Abl and p210Bcr-Abl, Tel-Abl, a novel fusion protein resulting from a diffe rent chromosomal translocation, has recently been described. In this study, the kinase specificities of the Bcr-Abl and Tel-Abl proteins were compared to the physiological Abl family kinases c-Abl and Arg (nhl related gene). Using short peptides which correspond to the target epitopes in known subst rate proteins of Abl family kinases, we found a higher catalytic promiscuit y of Bcr-Abl and Tel-Abl. Similar to Bcr-Abl, Tel-Abl was found in complexe s with the adapter protein CRKL. In addition, c-Crk II and CRKL are tyrosin e phosphorylated and complexed with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3 cells. GTPase analysis with a Ras GTP- specific precipitation assay showed constitutive elevation of GTP-loaded Ra s in cells expressing the leukaemic Abl proteins. The mitogenic MAPK/Erk ki nases as well as Akt/PKB, a kinase implicated to negatively regulate apopto sis, were also constitutively activated by both Bcr-Abl and Tel-Abl, The re sults indicate that the leukaemic Abl-fusion proteins have catalytic specif icities different from the normal kinases c-Abl and Arg and that Tel-Abl is capable to activate at least some pathways which are also upregulated by B cr-Abl.