BCR-ABL mediates arsenic trioxide-induced apoptosis independently of its aberrant kinase activity

Puccetti, Elena, Güller, Saskia, Orleth, Anette, Brüggenolte, Nicole, Hoelzer, Dieter, Ottmann, Oliver Gerhard ORCID: https://orcid.org/0000-0001-9559-1330 and Ruthardt, Martin ORCID: https://orcid.org/0000-0003-1021-3811 2000. BCR-ABL mediates arsenic trioxide-induced apoptosis independently of its aberrant kinase activity. Cancer Research 60 (13) , 3409–3413.

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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/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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association for Cancer Research
ISSN:	0008-5472
Date of Acceptance:	17 May 2000
Last Modified:	01 Mar 2024 15:15
URI:	https://orca.cardiff.ac.uk/id/eprint/166048

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