THE DIMERIZATION PROPERTY OF GLUTATHIONE-S-TRANSFERASE PARTIALLY REACTIVATES BCR-ABL LACKING THE OLIGOMERIZATION DOMAINS

Bcr-Abl oncoproteins are responsible for the pathogenesis of human leu kemias with a reciprocal chromosome translocation t(9;22). The amino-t erminal Bcr sequence has a potential to form a homotetramer (tetramer domain), and destructions of the tetramer domain cause a complete loss of biological activities in Bcr-Abl. Here we show that Bcr-Abl in whi ch the tetramer domain is replaced with glutathione S-transferase (GST ) with a dimerizing ability (GST/Bcr-Abl-(Delta 1-160)) can no longer induce an interleukin-3 (IL-3) independence in Ba/F3 cells or transfor m mouse bone marrow cells but still retains by 30-40% the ability to t ransform Rat1 cells, Compared with the wild type Bcr-Abl, autophosphor ylation of GST/Bcr-Abl-(Delta 1-160) in vivo was reduced by more than 50%. The Grb-2 binding to GST/Bcr-Abl-(Delta 1-160) was 50% reduced in Rat1 cells and undetectable in Ba/F3 cells. In Rat1 cells expressing GST/Bcr-Abl-(Delta 1-160), phosphotyrosine contents of p62 and She wer e 70% decreased.