MiR-130a is aberrantly overexpressed in adult acute myeloid leukemia with t(8;21) and its suppression induces AML cell death

Chao  Ding; Su-Ning  Chen; Roderick A. F.  Macleod; Hans G.  Drexler; Stefan  Nagel; De-Pei  Wu; Ai-Ning  Sun; Hai-Ping  Dai

doi:10.1080/03009734.2018.1440037

Chao Ding Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China
Su-Ning Chen Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People’s Republic of China
Roderick A. F. Macleod Leibniz Institute DSMZ–German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
Hans G. Drexler Leibniz Institute DSMZ–German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
Stefan Nagel Leibniz Institute DSMZ–German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany
De-Pei Wu Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People’s Republic of China; Suzhou Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, People’s Republic of China
Ai-Ning Sun Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People’s Republic of China; Suzhou Institute of Blood and Marrow Transplantation, Soochow University, Suzhou, People’s Republic of China
Hai-Ping Dai Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; Collaborative Innovation Center of Hematology, Soochow University, Suzhou, People’s Republic of China; Leibniz Institute DSMZ–German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany http://orcid.org/0000-0003-1125-7744

DOI: https://doi.org/10.1080/03009734.2018.1440037

Keywords: Acute myeloid leukemia, miR-130a, t(8;21), outcome, overexpression

Abstract

Background: Emerging evidence has revealed that miRNAs can function as oncogenes or tumor suppressor genes in leukemia. The ectopic expression of miR-130a has been reported in chronic leukemia, but our understanding of the biological implications of miR-130a expression remains incomplete.

Methods: We quantified a cohort of de novo acute myeloid leukemia (AML) by bead-based miRNA and real-time quantitative PCR (Rq-PCR). The luciferase reporter gene assay was analyzed after the plasmid constructs which contain 5’-UTR of miR-130a and a Renilla luciferase reporter plasmid were transfected simultaneously into 293T cells. MTT and caspase 3/7 apoptosis assays were used to test cell viability and apoptosis.

Results: We identified miR-130a as significantly overexpressed in t(8;21) AML. Expression of miR-130a decreased significantly once patients with t(8;21) achieved complete remission, but increased sharply at the time of relapse. In patients with t(8;21) AML, KIT mutational status was associated with miR-130a expression—with higher expression associated with KIT activating mutations. Increased miR-130a expression in t(8;21) AML was associated with slightly worse event-free survival; however, no impact on overall survival was observed. Knockdown of AML1/ETO protein in the SKNO-1 cell line resulted in decrease of expression of miR-130a. Direct binding of AML1/ETO fusion protein with the promoter sequence of miR-130a was detected with luciferase reporter gene assay. Following miR-130a knockdown, SKNO-1 demonstrated increased sensitivity to etoposide.

Conclusions: Our data suggest that miR-130a is directly activated by AML1/ETO, and may act as a factor which is associated with leukemia burden, event-free survival, and chemotherapy sensitivity in t(8;21) AML.

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