Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML.
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.
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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D
Malani
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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A
Murumägi
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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B
Yadav
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
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M
Kontro
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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S
Eldfors
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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A
Kumar
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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Karjalainen
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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MM
Majumder
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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P
Ojamies
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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Pemovska
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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K
Wennerberg
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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C
Heckman
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
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K
Porkka
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
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M
Wolf
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.|Department of Mathematics and Statistics, University of Turku, Turku, Finland.
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Aittokallio
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.|Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden.
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Kallioniemi
D000328:Adult; D003561:Cytarabine / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D005938:Glucocorticoids; D003561:Cytarabine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3