Activation of cellular proto-oncogenes as a result of chromosomal abnormalities has been implicated in the development of some human malignancies. Perhaps one of the most striking examples of this association occurs in chronic myelogenous leukaemia, where the Philadelphia (Ph) translocation results in substitution of the 5' end of the c-abl proto-oncogene with bcr gene sequences. A unique hybrid bcr-abl message is produced. As the Ph translocation is also present in some patients with acute lymphoblastic leukaemia, we initiated studies to determine if similar genomic events occur in these two different forms of Ph-positive leukaemia. Here we report that the Ph translocation in acute lymphoblastic leukaemia can result in production of a novel aberrant c-abl protein that is distinct from the bcr-abl protein found in Ph-positive chronic myelogenous leukaemia. Our observations suggest that alternative mechanisms of activation of c-abl exist, and may be important in the development of human acute lymphoid rather than chronic myeloid malignancies.

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Activation of the cellular oncogene ras has been implicated in many types of human malignancies. In this study, the relative levels of p21 protein product of ras (p2lr") in primary and metastatic colon tumors were compared to those in adjacent normal tissues. Nine of the 17 primary tumors had substantially elevated levels of p2lr, with respect to adjacent normal tissues. Eight of these tumors were from Dukes' B and C stages. Four of the five tumors classified as "D" stage (in which distant metastases are present) did not show elevated levels of p21r,. In metastases from primary colon tumors, nine of nine were considerably reduced in p2l' expression regardless of the site of metastasis. These data suggest that elevation of p2lr" may be a common event in early stages of colon tumors, and tumor progression may lead to a more autonomous population of cells in which other growth factors supplant the role of this protein.

A protein identified as P859'9-°was shown to be phosphorylated when immunoprecipitates from tsllO Moloney murine sarcoma virus transformed nonproducer cells (clone 6m2) were incubated with [y-32P]ATP. The in vitro-labeled 85,000-dalton phosphoprotein comigrated on NaDodSO4/polyacrylamide gels with authentic phosphorylated P859'9-°. Immunoprecipitates obtained with antisera prepared against Rauscher murine leukemia virus core protein p30 were active in the immune complex kinase assay but anti-murine leukemia virus plO precipitates were not. Previous studies have shown that anti-p30 but not antiplO antisera recognize P859'9-°. The 6m2 clone has been shown to express P85gag-"w8 at 330C but not at 39TC. Anti-p30 immune complexes from 6m2 cells maintained at 390C failed to phosphorylate the 85,000-dalton protein. Furthermore, the in vitro phosphorylated 85,000-dalton protein gave the same pattern of V8 protease-generated cleavage products as in vivo 32P-labeled P85gag-'.8, We conclude from these results that P85gag`m06 is phosphorylated in anti-p30 immune complex kinase reactions. Phosphoamino acid analyses indicated that the in vitro phosphorylated P85gag-tno contained phosphoserine and phosphothreonine. Our findings indicate that incubation of anti-p30 immunoprecipitates at 39°C drastically reduced, in a specific way, the kinase activity associated with P85gag-1l8. This result and other data suggest that the kinase is virus-encoded. Because P85gag-"1w8, but not Pr65gag, is phosphorylated in anti-p30 immunoprecipitates from MuLVMuSV tsllO producer cells, the kinase enzyme is associated with P85gag-' and not gag gene products. A second major polypeptide of the size of P58gag was also phosphorylated in anti-p30 immunoprecipitates from cells maintained at 33°C but not at 39°C. Since 6m2 cells at 39°C contain P58wag, this is also consistent with the kinase activity being associated with P85gag-11W.