Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic-induced apoptosis.

Puccetti, Elena, Beissert, Tim, Güller, Saskia, Li, Jun E, Hoelzer, Dieter, Ottmann, Oliver G ORCID: https://orcid.org/0000-0001-9559-1330 and Ruthardt, Martin ORCID: https://orcid.org/0000-0003-1021-3811 2003. Leukemia-associated translocation products able to activate RAS modify PML and render cells sensitive to arsenic-induced apoptosis. Oncogene 22 , 6900–6908. 10.1038/sj.onc.1206747

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Abstract

Since the 19th century, arsenic (As2O3) has been used in the treatment of chronic myelogenous leukemia (CML) characterized by the t(9;22) translocation. As2O3 induces complete remissions in patients with acute promyelocytic leukemia. The response to As2O3 is genetically determined by the t(15;17)-or the t(9;22)-specific fusion proteins PML/RARalpha or BCR/ABL. The PML portion of PML/RARalpha is crucial for the sensitivity to As2O3. PML is nearly entirely contained in PML/RARalpha. PML is upregulated by oncogenic RAS in primary fibroblasts. The aberrant kinase activity of BCR/ABL leads to constitutive activation of RAS. Therefore, we hypothesized that BCR/ABL could increase sensitivity to As2O2-induced apoptosis by modifying PML expression. To disclose the mechanism of As2O3-induced apoptosis in PML/RARalpha- and BCR/ABL-expressing cells, we focused on the role of PML for As2O3-induced cell death. Here we report that (i) sensitivity to As2O3-induced apoptosis of U937 cells can be increased either by overexpression of PML, or by conditional expression of activated RAS; (ii) also the expression of the t(8;21)-related AML-1/ETO increased sensitivity to As2O3-induced apoptosis; (iii) both BCR/ABL and AML-1/ETO activated RAS and modified the PML expression pattern; (iv) the expression of either BCR/ABL or AML-1/ETO rendered U937 cells sensitive to interferon alpha-induced apoptosis. In summary, these data suggest a crucial role of factors able to upregulate PML for As2O2-induced cell death.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Springer Nature [academic journals on nature.com]
ISSN:	0950-9232
Date of Acceptance:	30 April 2003
Last Modified:	29 Feb 2024 10:15
URI:	https://orca.cardiff.ac.uk/id/eprint/166056

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