The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity

The product of the Philadelphia chromosome (Ph) translocation, the BCR/ABL oncogene, exists in three principal forms (P190, P210, and P230 BCR/ABL) th at are found in distinct forms of Ph-positive leukemia, suggesting the thre e proteins have different leukemogenic activity. We have directly compared the tyrosine kinase activity, in vitro transformation properties, and in vi vo leukemogenic activity of the P190, P210, and P230 forms of BCR/ABL. P230 exhibited lower intrinsic tyrosine kinase activity than P210 and P190. Alt hough all three oncogenes transformed both myeloid (32D cl3) and lymphoid ( Ba/F3) interleukin (IL)3-dependent cell lines to become independent of IL-3 for survival and growth, their ability to stimulate proliferation of Ba/F3 lymphoid cells differed and correlated directly with tyrosine kinase activ ity. In a murine bone marrow transduction/transplantation model, the three forms of BCR/ABL were equally potent in the induction of a chronic myeloid leukemia (CML)-like myeloproliferative syndrome in recipient mice when 5-fl uorouracil (5-FU)-treated donors were used. Analysis of proviral integratio n showed the CML-like disease to be polyclonal and to involve multiple myel oid and B lymphoid lineages, implicating a primitive multipotential target cell. Secondary transplantation revealed that only certain minor clones gav e rise to day 12 spleen colonies and induced disease in secondary recipient s, suggesting heterogeneity among the target cell population. In contrast, when marrow from non-5-FU-treated donors was used, a mixture of CML-like di sease, B lymphoid acute leukemia, and macrophage tumors was observed in rec ipients. P190 BCR/ABL induced lymphoid leukemia with shorter latency than P 210 or P230. The lymphoid leukemias and macrophage tumors had provirus inte gration patterns that were oligo- or monoclonal and limited to the tumor ce lls, suggesting a lineage-restricted target cell with a requirement for add itional events in addition to BCR/ABL transduction for full malignant trans formation. These results do not support the hypothesis that P230 BCR/ABL in duces a distinct and less aggressive form of CML in humans, and suggest tha t the rarity of P190 BCR/ABL in human CML may reflect frequent BCR intron 1 breakpoints during the genesis of the Ph chromosome in stem cells, rather than intrinsic differences in myeloid leukemogenicity between P190 and P210 .