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.
Highlights
The vast majority of pediatric acute myeloid leukemia (AML) patients achieves complete remission with current intensive chemotherapy protocols [1]
We tested primary blast cells of de novo pediatric AML patients for ex vivo response towards the chemotherapeutic agents AML blasts towards cytarabine (Ara C) (n = 121), DNR (n = 119), cladribine (2-CdA) (n = 103) and VP16 (n = 70), which are used for the treatment of AML routinely, or in trial setting [35,36,37]
Ex vivo drug response varied among karyotype groups, with the most apparent differences observed towards 2-CdA (Kruskal-Wallis p = 0.063, Figure A2)
Summary
The vast majority of pediatric acute myeloid leukemia (AML) patients achieves complete remission with current intensive chemotherapy protocols [1]. 60–70% of these patients achieve second complete remission [4], salvage therapy often results in short- and long-term side effects. Reducing the requirement for salvage therapy is desirable. Several approaches to prevent relapse may be effective. One could focus on suppression of resistant clones harboring targetable mutations that may have been selected during induction chemotherapy [5], e.g., using FLT3 or IDH1/2 inhibitors [6,7], which requires additional monitoring of clonal heterogeneity at diagnosis and in complete remission. An alternative approach to prevent relapse is the eradication of all leukemic cells with initial (combination) therapy
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