Dataset Information

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML.

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.

SUBMITTER: Malani D

PROVIDER: S-EPMC5420795 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML.

Malani D D Murumägi A A Yadav B B Kontro M M Eldfors S S Kumar A A Karjalainen R R Majumder M M MM Ojamies P P Pemovska T T Wennerberg K K Heckman C C Porkka K K Wolf M M Aittokallio T T Kallioniemi O O

Leukemia 20161111 5

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 uncov ...[more]

PMID: 27833094

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Project description:Lysine methyltransferase 2A (KMT2A, also known as MLL) translocations (MLL‑t) are frequently associated with mutations in RAS pathway genes in acute myeloid leukemia (AML). Previous findings with a mouse model showed that cooperation of MLL/AF10 with tyrosine‑protein phosphatase non‑receptor type 11 (PTPN11)G503A accelerated leukemia development, but increased cytarabine (Ara‑C) sensitivity of leukemia cells. To identify the genes responsible for reduced survival and Ara‑C resistance, transcriptomic profiling between six pairs of mouse MLL/AF10(OM‑LZ) leukemia cells harboring activating and wild‑type KRAS or PTPN11 was compared. A total of 23 differentially expressed genes (DEGs) with >1.5‑fold‑change between the paired cell lines were identified. The Gene Ontology (GO) terms overrepresented in these 23 DEGs included 'immune system process', 'actin filament binding', 'cellular response to interferon‑alpha' and 'sequence‑specific DNA'. Among the four genes (Hoxa11, PR domain zinc finger protein 5, Iroquois‑class homeodomain protein IRX‑5 and homeobox protein PKNOX2) mapped to the GO term 'sequence‑specific DNA', HOXA11 upregulation was associated with AML harboring MLL‑t and RAS signaling mutations based on a meta‑analysis using data deposited in Oncomine™ and analysis of the clinical samples in the present study. Microarray data revealed that only Hoxa11 was upregulated in those cells harboring activating PTPN11. Functional studies of Hoxa11 knockdown or overexpression in MLL/AF10(OM‑LZ) cells revealed that Hoxa11 expression levels were associated with survival in vivo and Ara‑C sensitivity/apoptosis in vitro. In addition, Hoxa11 regulated the expression of the apoptosis‑related genes, NF‑κB inhibitor α, transcription factor p65 and transformation‑related protein p53. Furthermore, the results of a meta‑analysis using Heuser's AML dataset supported the finding that chemotherapy responders have higher expression levels of HOXA11. These results indicated that the expression of HOXA11 increased cell apoptosis and predicted an improved response to Ara‑C in AML.

Dataset Information

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML.

Publications

Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML.

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