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J. Exp. Med.,
Volume 189, Number 9, May 3, 1999 1399-1412
By
From the * Center for Blood Research, Department of Genetics, Harvard Medical School, Boston,
Massachusetts 02115; the The product of the Philadelphia chromosome (Ph) translocation, the BCR/ABL oncogene, exists
in three principal forms (P190, P210, and P230 BCR/ABL) that are found in distinct forms of
Ph-positive leukemia, suggesting the three proteins have different leukemogenic activity. We
have directly compared the tyrosine kinase activity, in vitro transformation properties, and in vivo
leukemogenic activity of the P190, P210, and P230 forms of BCR/ABL. P230 exhibited lower intrinsic tyrosine kinase activity than P210 and P190. Although 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 activity. 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-fluorouracil (5-FU)-treated donors were used. Analysis of proviral integration showed the
CML-like disease to be polyclonal and to involve multiple myeloid and B lymphoid lineages, implicating a primitive multipotential target cell. Secondary transplantation revealed that only certain minor clones gave rise to day 12 spleen colonies and induced disease in secondary recipients,
suggesting heterogeneity among the target cell population. In contrast, when marrow from non-
5-FU-treated donors was used, a mixture of CML-like disease, B lymphoid acute leukemia, and macrophage tumors was observed in recipients. P190 BCR/ABL induced lymphoid leukemia
with shorter latency than P210 or P230. The lymphoid leukemias and macrophage tumors had
provirus integration patterns that were oligo- or monoclonal and limited to the tumor cells, suggesting a lineage-restricted target cell with a requirement for additional events in addition to
BCR/ABL transduction for full malignant transformation. These results do not support the hypothesis that P230 BCR/ABL induces a distinct and less aggressive form of CML in humans, and
suggest that the rarity of P190 BCR/ABL in human CML may reflect infrequent 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.
Division of Adult Oncology, Department of Medicine, Dana-Farber
Cancer Institute, Boston, Massachusetts 02115; and the § Whitehead Institute for Biomedical
Research, Cambridge, Massachusetts 02142
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