Oncotarget

Research Papers:

XIAP inhibitors induce differentiation and impair clonogenic capacity of acute myeloid leukemia stem cells

Daniel Moreno-Martínez, Meritxell Nomdedeu, María Carmen Lara-Castillo, Amaia Etxabe, Marta Pratcorona, Niccolò Tesi, Marina Díaz-Beyá, María Rozman, Emili Montserrat, Álvaro Urbano-Ispizua, Jordi Esteve and Ruth M. Risueño _

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Oncotarget. 2014; 5:4337-4346. https://doi.org/10.18632/oncotarget.2016

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Abstract

Daniel Moreno-Martínez1, Meritxell Nomdedeu1,2,3, María Carmen Lara-Castillo1, Amaia Etxabe1, Marta Pratcorona2,3, Niccolò Tesi1, Marina Díaz-Beyá2,3, María Rozman4, Emili Montserrat2,3, Álvaro Urbano-Ispizua1,2,3, Jordi Esteve1,2,3, Ruth M. Risueño1

1 Josep Carreras Leukaemia Research Institute. Barcelona, Spain

2 Department of Hematology, Hospital Clínic de Barcelona. Barcelona, Spain

3 Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain

4 Department of Hematopathology, Hospital Clínic de Barcelona, Barcelona, Spain

Correspondence:

Ruth M. Risueño, email:

Keywords: Acute myeloid leukemia, leukemic stem cell, new drugs, XIAP, Embelin

Received: March 17, 2014 Accepted: May 26, 2014 Published: May 26, 2014

Abstract

Acute myeloid leukemia (AML) is a neoplasia characterized by the rapid expansion of immature myeloid blasts in the bone marrow, and marked by poor prognosis and frequent relapse. As such, new therapeutic approaches are required for remission induction and prevention of relapse. Due to the higher chemotherapy sensitivity and limited life span of more differentiated AML blasts, differentiation-based therapies are a promising therapeutic approach. Based on public available gene expression profiles, a myeloid-specific differentiation-associated gene expression pattern was defined as the therapeutic target. A XIAP inhibitor (Dequalinium chloride, DQA) was identified in an in silico screening searching for small molecules that induce similar gene expression regulation. Treatment with DQA, similarly to Embelin (another XIAP inhibitor), induced cytotoxicity and differentiation in AML. XIAP inhibition differentially impaired cell viability of the most primitive AML blasts and reduced clonogenic capacity of AML cells, sparing healthy mature blood and hematopoietic stem cells. Taken together, these results suggest that XIAP constitutes a potential target for AML treatment and support the evaluation of XIAP inhibitors in clinical trials.


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