TY - JOUR
T1 - Mir-10a overexpression is associated with npm1 mutations and mdm4 downregulation in intermediate-risk acute myeloid leukemia
AU - Ovcharenko, Dmitriy
AU - Stölzel, Friedrich
AU - Poitz, David
AU - Fierro, Fernando A
AU - Schaich, Markus
AU - Neubauer, Andreas
AU - Kelnar, Kevin
AU - Davison, Timothy
AU - Müller-Tidow, Carsten
AU - Thiede, Christian
AU - Bornhäuser, Martin
AU - Ehninger, Gerhard
AU - Brown, David
AU - Illmer, Thomas
PY - 2011/10
Y1 - 2011/10
N2 - Objective: The study investigated differential microRNA (miRNA) expression patterns in acute myeloid leukemia (AML) patients with intermediate-risk (IR) characteristics. After characterization and validation of miR-10a, which was specifically upregulated in nucleophosmin 1 (NPM1) mutant AML samples, functional consequences of miR-10a overexpression were further delineated in vitro. Materials and Methods: Microarray analysis of miRNAs in bone marrow samples from AML (IR) patients with NPM1 mutations and healthy donors was performed to detect differential expression patterns. After validation of miRNA expression specific for NPM1 mutation in AML patients by quantitative reverse transcription polymerase chain reaction, a functional target gene search was conducted using complementary DNA microarray data from samples transfected with miR-10a. Potential target gene validation was done using transient transfection of K562 cells followed by Western blotting and luciferase reporter assay. Results: In comparison with wild-type samples, NPM1 mutant AML samples were shown to markedly overexpress miR-10a. Subsequent in vitro miR-10a overexpression induced differential gene expression as determined by microarray analysis. Here the murine double minute 4 (MDM4) gene turned out as a candidate gene for miR-10a. Validation of MDM4 in leukemic cells revealed a robust negative relationship between miR-10a overexpression and MDM4 downregulation. Furthermore, we determined an inverse association between miR-10a and MDM4 expression in AML (IR) samples with respect to their NPM1 mutational status. Conclusions: miR-10a expression is highly characteristic for AML (IR) patients with NPM1 mutations and may influence its biological properties in AML by interfering with the p53 machinery partly regulated by MDM4.
AB - Objective: The study investigated differential microRNA (miRNA) expression patterns in acute myeloid leukemia (AML) patients with intermediate-risk (IR) characteristics. After characterization and validation of miR-10a, which was specifically upregulated in nucleophosmin 1 (NPM1) mutant AML samples, functional consequences of miR-10a overexpression were further delineated in vitro. Materials and Methods: Microarray analysis of miRNAs in bone marrow samples from AML (IR) patients with NPM1 mutations and healthy donors was performed to detect differential expression patterns. After validation of miRNA expression specific for NPM1 mutation in AML patients by quantitative reverse transcription polymerase chain reaction, a functional target gene search was conducted using complementary DNA microarray data from samples transfected with miR-10a. Potential target gene validation was done using transient transfection of K562 cells followed by Western blotting and luciferase reporter assay. Results: In comparison with wild-type samples, NPM1 mutant AML samples were shown to markedly overexpress miR-10a. Subsequent in vitro miR-10a overexpression induced differential gene expression as determined by microarray analysis. Here the murine double minute 4 (MDM4) gene turned out as a candidate gene for miR-10a. Validation of MDM4 in leukemic cells revealed a robust negative relationship between miR-10a overexpression and MDM4 downregulation. Furthermore, we determined an inverse association between miR-10a and MDM4 expression in AML (IR) samples with respect to their NPM1 mutational status. Conclusions: miR-10a expression is highly characteristic for AML (IR) patients with NPM1 mutations and may influence its biological properties in AML by interfering with the p53 machinery partly regulated by MDM4.
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U2 - 10.1016/j.exphem.2011.07.008
DO - 10.1016/j.exphem.2011.07.008
M3 - Article
C2 - 21784052
AN - SCOPUS:80052855368
VL - 39
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
IS - 10
ER -