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Leukemia. 2017 May;31(5):1187-1195. doi: 10.1038/leu.2016.314. Epub 2016 Nov 11.

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML.

Author information

1
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
2
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
3
Department of Mathematics and Statistics, University of Turku, Turku, Finland.
4
Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden.

Abstract

We sought to identify drugs that could counteract cytarabine resistance in acute myeloid leukemia (AML) by generating eight resistant variants from MOLM-13 and SHI-1 AML cell lines by long-term drug treatment. These cells were compared with 66 ex vivo chemorefractory samples from cytarabine-treated AML patients. The models and patient cells were subjected to genomic and transcriptomic profiling and high-throughput testing with 250 emerging and clinical oncology compounds. Genomic profiling uncovered deletion of the deoxycytidine kinase (DCK) gene in both MOLM-13- and SHI-1-derived cytarabine-resistant variants and in an AML patient sample. Cytarabine-resistant SHI-1 variants and a subset of chemorefractory AML patient samples showed increased sensitivity to glucocorticoids that are often used in treatment of lymphoid leukemia but not AML. Paired samples taken from AML patients before treatment and at relapse also showed acquisition of glucocorticoid sensitivity. Enhanced glucocorticoid sensitivity was only seen in AML patient samples that were negative for the FLT3 mutation (P=0.0006). Our study shows that development of cytarabine resistance is associated with increased sensitivity to glucocorticoids in a subset of AML, suggesting a new therapeutic strategy that should be explored in a clinical trial of chemorefractory AML patients carrying wild-type FLT3.

PMID:
27833094
PMCID:
PMC5420795
DOI:
10.1038/leu.2016.314
[Indexed for MEDLINE]
Free PMC Article

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