Ngankeu Apollinaire, Ranganathan Parvathi, Havelange Violaine, Nicolet Deedra, Volinia Stefano, Powell Bayard L, Kolitz Jonathan E, Uy Geoffrey L, Stone Richard M, Kornblau Steven M, Andreeff Michael, Croce Carlo M, Bloomfield Clara D, Garzon Ramiro
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Hematological Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Oncotarget. 2017 Dec 12;9(4):4354-4365. doi: 10.18632/oncotarget.23150. eCollection 2018 Jan 12.
We previously reported that microRNA (miR)-29b is down-regulated and has a tumor suppressor role in acute myeloid leukemia (AML). However, little is known about the mechanisms responsible for miR-29b expression downregulation in AML. In this work we screened for mutations that could affect miR-29b expression. Using Sanger sequencing, we identified a germline thymidine (T) base deletion within the miR-29b-1/miR-29a cluster precursor in 16% of AML patients. Remarkably we found a significant enrichment for the presence of the miR-29 polymorphism in core binding factor (CBF) newly diagnosed AML patients ( = 61/303; 20%) with respect to age, sex and race matched controls ( = 43/402:11%, < 0.01). Mechanistically, this polymorphism affects the expression ratio of mature miR-29b and miR-29a by dampening the processing of miR-29a. RNA immunoprecipitation assays showed reduced DROSHA binding capacity to the polymorphism with respect to the controls. Finally, we showed that this polymorphism negatively impacts the ability of miR-29b-1/miR-29a cluster to target and , both known miR-29 targets.
我们之前报道过，微小RNA（miR）-29b在急性髓系白血病（AML）中表达下调并具有肿瘤抑制作用。然而，关于AML中miR-29b表达下调的机制知之甚少。在这项研究中，我们筛选了可能影响miR-29b表达的突变。通过桑格测序，我们在16%的AML患者中发现了miR-29b-1/miR-29a簇前体中的一个种系胸腺嘧啶（T）碱基缺失。值得注意的是，我们发现与年龄、性别和种族匹配的对照组相比，新诊断的核心结合因子（CBF）AML患者（n = 61/303；20%）中miR-29多态性的存在显著富集（n = 43/402：11%，P < 0.01）。从机制上讲，这种多态性通过抑制miR-29a的加工来影响成熟miR-29b和miR-29a的表达比例。RNA免疫沉淀分析显示，与对照组相比，DROSHA与该多态性的结合能力降低。最后，我们表明这种多态性对miR-29b-1/miR-29a簇靶向两个已知的miR-29靶点ETS1和RUNX的能力产生负面影响。
