title: XIAP inhibitors induce differentiation and impair clonogenic capacity of acute myeloid leukemia stem cells.
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.
authors: Josep Carreras Leukaemia Research Institute. Barcelona, Spain.
authors: Daniel
authors: D
authors: Moreno-Martínez
authors: Meritxell
authors: M
authors: Nomdedeu
authors: María Carmen
authors: MC
authors: Lara-Castillo
authors: Amaia
authors: A
authors: Etxabe
authors: Marta
authors: M
authors: Pratcorona
authors: Niccolò
authors: N
authors: Tesi
authors: Marina
authors: M
authors: Díaz-Beyá
authors: María
authors: M
authors: Rozman
authors: Emili
authors: E
authors: Montserrat
authors: Alvaro
authors: A
authors: Urbano-Ispizua
authors: Jordi
authors: J
authors: Esteve
authors: Ruth M
authors: RM
authors: Risueño
mesh_terms: D000328:Adult; D016923:Cell Death; D002454:Cell Differentiation; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein