Harnessing gene expression profiles for the identification of ex vivo drug response genes in pediatric acute myeloid leukemia

David G.J. Cucchi, Costa Bachas, Marry M. van den Heuvel-Eibrink, Susan T.C.J.M. Arentsen-Peters, Zinia J. Kwidama, Gerrit J. Schuurhuis, Yehuda G. Assaraf, Valérie de Haas, Gertjan J.L. Kaspers, Jacqueline Cloos*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Novel treatment strategies are of paramount importance to improve clinical outcomes in pediatric AML. Since chemotherapy is likely to remain the cornerstone of curative treatment of AML, insights in the molecular mechanisms that determine its cytotoxic effects could aid further treatment optimization. To assess which genes and pathways are implicated in tumor drug resistance, we correlated ex vivo drug response data to genome-wide gene expression profiles of 73 primary pediatric AML samples obtained at initial diagnosis. Ex vivo response of primary AML blasts towards cytarabine (Ara C), daunorubicin (DNR), etoposide (VP16), and cladribine (2-CdA) was associated with the expression of 101, 345, 206, and 599 genes, respectively (p < 0.001, FDR 0.004–0.416). Microarray based expression of multiple genes was technically validated using qRT-PCR for a selection of genes. Moreover, expression levels of BRE, HIF1A, and CLEC7A were confirmed to be significantly (p < 0.05) associated with ex vivo drug response in an independent set of 48 primary pediatric AML patients. We present unique data that addresses transcriptomic analyses of the mechanisms underlying ex vivo drug response of primary tumor samples. Our data suggest that distinct gene expression profiles are associated with ex vivo drug response, and may confer a priori drug resistance in leukemic cells. The described associations represent a fundament for the development of interventions to overcome drug resistance in AML, and maximize the benefits of current chemotherapy for sensitive patients.

Original languageEnglish
Article number1247
JournalCancers
Volume12
Issue number5
DOIs
Publication statusPublished - May 2020

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