Abstract
Cytarabine is the primary chemotherapeutic agent used for treatment of acute myeloid leukemia (AML). Disease relapse after initial remission remains one of the most pressing therapeutic challenges in the treatment of AML. Relapsed disease is often resistant to cytarabine and subsequent salvage therapy is ineffective. Recent studies have shown that some microRNAs (miRNAs) are associated with prognosis, but have not yet explored the role of miRNAs in cellular response to cytarabine. We identified 20 miRNAs that associate with the in vitro cytarabine chemo-sensitivity or apoptotic response of eight AML cell lines. Out of the 20 miRNAs, data on 18 miRNAs was available in AML patients from The Cancer Genome Atlas database. Our stepwise-integrated analyses (step 1 – miRNA–target mRNA that were significantly correlated in AML patients; step 2 – mRNAs from step 1 with significant association with overall survival (OS)) identified 23 unique miRNA–mRNA pairs predictive of OS in AML patients. As expected HOX genes (HOXA9, HOXB7, and HOXA10) were identified to be regulated by miRs as well as predictive of worse OS. Additionally, miR107-Myb, miR-378-granzyme B involved in granzyme signaling and miR10a-MAP4K4 were identified to be predictive of outcome through integrated analysis. Although additional functional validations to establish clinical/pharmacologic importance of miRNA–mRNA pairs are needed, our results from RNA electrophoretic mobility shift assay confirmed binding of miR-10a, miR-378, and miR-107 with their target genes GALNT1, GZMB, and MYB, respectively. Integration of pathogenic and pharmacologically significant miRNAs and miRNA–mRNA relationships identified in our study opens up opportunities for development of targeted/miRNA-directed therapies.
Highlights
Acute myeloid leukemia (AML) is a hematological malignancy characterized by the presence of immature abnormal myeloid cells in bone marrow
Based on the cytotoxicity area under the survival curve (AUC), HL-60, MV-4-11, KG-1, and ME1 were classified as sensitive, while MOLM-16, AML-193, Kasumi-1, and THP-1 were classified as resistant cell lines
Expression of miR-25-3p, miR-148b3p, miR-107, miR-374-5p, miR-425-5p were positively associated with AUC for cell survival post-cytarabine treatment and miR16-5p, miR-24-3p, miR-196a-5p, and miR-155-5p were negatively associated with AUC for cell survival post-cytarabine treatment (p < 0.05). (Selected miRNAs are shown in Supplementary Figure S2.) Expression levels of miR-10a-5p, miR-29a/b-3p, miR30e-5p, miR-33a-5p, miR-378a/g were positively and expression levels miR-197-3p, miR-27b-3p, miR-324-5p, and miR-421 were negatively associated with AUC for caspase-3/7 activation post cytarabine treatment (Table 2, p < 0.05)
Summary
Acute myeloid leukemia (AML) is a hematological malignancy characterized by the presence of immature abnormal myeloid cells in bone marrow It is a heterogeneous disease with various subtypes classified based on the morphology, immunophenotype, and cytogenetics that are associated with outcome (Döhner et al, 2010). Chemotherapeutic regimens including cytarabine induce complete response in 65–80% of AML patients, the majority of these patients suffer from disease relapse within 2 years of diagnosis (Cros et al, 2004). This can be partly attributed to the development of resistance of leukemic cells to cytarabine-based chemotherapy regimens (Montillo et al, 1998; Estey, 2000). Others have identified gene-expression differences between cytarabinesensitive and -resistant cell lines in order to understand the molecular mechanisms underlying cytarabine resistance (Abe et al, 2006; Song et al, 2009)
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