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BCR-ABL Mediates Arsenic Trioxide-induced Apoptosis Independently of Its Aberrant Kinase Activity¹

Medizinische Klinik III/Abteilung Hämatologie, Johann Wolfgang Goethe-Universität, D-60590 Frankfurt, Germany [E. P., S. G., N. B., D. H., O. G. O., M. R.], and Istituto di Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, Perugia University, 06100 Perugia, Italy [A. O.]

In the prechemotherapy era arsenic derivatives were used for treatment of chronic myelogenous leukemia, a myeloproliferative disorder characterized by the t(9;22) translocation, the Philadelphia chromosome (Ph+). In acute promyelocytic leukemia response to arsenic trioxide (As₂O₃) has been shown to be genetically determined by the acute promyelocytic leukemia-specific t(15;17) translocation product PML/RAR. Hence, we reasoned that As₂O₃ might have a selective inhibitory effect on proliferation of BCR-ABL-expressing cells.

Here, we report that: (a) As₂O₃ induced apoptosis in Ph+ but not in Ph- lymphoblasts; (b) enforced expression of BCR-ABL in U937 cells dramatically increased the sensitivity to As₂O₃; (c) the effect of As₂O₃ was independent of BCR-ABL kinase activity; and (d) As₂O₃ reduced proliferation of chronic myelogenous leukemia blasts but not of peripheral CD34+ progenitors. In summary, these data establish As₂O₃ as a tumor cell-specific agent, making its clinical application in Ph+ leukemia feasible.

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