BCR-ABL Mediates Arsenic Trioxide-induced Apoptosis Independently of Its Aberrant Kinase Activity
E Puccetti, S Güller, A Orleth, N Brüggenolte… - Cancer research, 2000 - AACR
E Puccetti, S Güller, A Orleth, N Brüggenolte, D Hoelzer, OG Ottmann, M Ruthardt
Cancer research, 2000•AACRIn 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/RARα. Hence,
we reasoned that As2O3 might have a selective inhibitory effect on proliferation of BCR-ABL …
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/RARα. Hence,
we reasoned that As2O3 might have a selective inhibitory effect on proliferation of BCR-ABL …
Abstract
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/RARα. 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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