Cell lines and clinical isolates derived from Ph¹-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration

The Philadelphia chromosome (Ph¹), observed in >90% of chronic myelogenous leukemia (CML) patients, results from a specific chromosomal translocation involving the c-abl gene. The translocation breakpoint occurs near c-abl and correlates with the production of an altered c-abl mRNA. In the CML-derived cell line K562, pH¹ is accompanied by a structurally altered c-abl protein (P210(c-abl)) with in vitro tyrosine kinase activity not detected with the normal c-abl protein (P145(c-abl)). We have examined c-abl proteins in other Ph¹-positive CML cell lines and found that they all express P210(c-abl). P210(c-abl) was also detected in bone marrow cells from CML patients with Ph¹ in the accelerated and blast crisis phases of the disease. Comparison of the [³⁵S]methionine-labeled tryptic peptides generated from the normal P145(c-abl) and P210(c-abl) showed that they have closely related structures, but additional polypeptide sequences are present in P210(c-abl). Based on these results we propose that translocation of c-abl in Ph¹-positive CML results in the creation of a chimeric gene leading to the production of a structurally altered c-abl protein with activated tyrosine kinase activity. The altered P210 c-abl protein is strongly implicated in the pathogenesis of CML.