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Garcia-Orti L, Cristobal I, Cirauqui C, Guruceaga E, Marcotegui N, Calasanz MJ, et al. Integration of SNP and mRNA Arrays with MicroRNA Profiling Reveals That MiR-370 Is Upregulated and Targets NF1 in Acute Myeloid Leukemia. PLoS ONE 2012;7(10):e47717
Background: Deregulated miRNA expression plays a crucial role in carcinogenesis. Recent studies show different
mechanisms leading to miRNA deregulation in cancer; however, alterations affecting miRNAs by DNA copy number
variations (CNV) remain poorly studied.
Results: Our integrative analysis including data from high resolution SNPs arrays, mRNA expression arrays, and miRNAs
expression profiles in 16 myeloid cell lines highlights that CNV are alternative mechanisms to deregulate the expression of
miRNAs in acute myeloid leukemia (AML), and represent a novel approach to identify novel candidate genes involved in
AML. We found association between the expression levels of 19 miRNAs and CNVs affecting their loci. Functional analysis
showed that NF1 is a direct target of miR-370, and that overexpression of miR-370 has similar effects that NF1 inactivation,
increasing proliferation and colony formation in AML cells. Moreover, real time RT-PCR showed that NF1 downregulation is a
recurrent event in AML (30.8%), and western blot analysis confirmed this result. MiR-370 overexpression and deletions
affecting the NF1 locus were identified as alternative mechanisms to downregulate NF1.
Conclusions: NF1 downregulation is a common event in AML, and both deletions in the NF1 locus and overexpression of
miR-370 are alternative mechanisms to downregulate NF1 in this disease. Our results suggest a leukemogenic role of miR-
370 through NF1 downregulation in AML cells. Since NF1 deficiency leads to RAS activation, patients with AML and
overexpression of miR-370 may potentially benefit from additional treatment with either RAS or mTOR inhibitors.