BCR-ABL mediates arsenic trioxide-induced apoptosis independently of its aberrant kinase activity.
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/RARalpha. 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.
Medizinische Klinik III/Abteilung Hämatologie, Johann Wolfgang Goethe-Universität, Frankfurt, Germany.
E
E
Puccetti
S
S
Güller
A
A
Orleth
N
N
Brüggenolte
D
D
Hoelzer
O G
OG
Ottmann
M
M
Ruthardt
D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001752:Blast Crisis / Q000473:pathology; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D010677:Philadelphia Chromosome; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D000077237:Arsenic Trioxide