Endogenous Tumor Suppressor microRNA-193b: Therapeutic and Prognostic Value in Acute Myeloid Leukemia

被引：57

作者：

Bhayadia, Raj ^{[1
,2
]}

Krowiorz, Kathrin ^{[3
]}

Haetscher, Nadine ^{[4
]}

Jammal, Razan ^{[1
]}

Emmrich, Stephan ^{[1
]}

Obulkasim, Askar ^{[8
]}

Fiedler, Jan ^{[1
]}

Schwarzer, Adrian ^{[1
]}

Rouhi, Arefeh ^{[3
]}

Heuser, Michael ^{[1
]}

Wingert, Susanne ^{[4
]}

Bothur, Sabrina ^{[4
,5
,6
]}

Doehner, Konstanze ^{[3
]}

Maetzig, Tobias ^{[10
]}

Ng, Michelle ^{[1
,2
]}

Reinhardt, Dirk ^{[7
]}

Doehner, Hartmut ^{[3
]}

Zwaan, C. Michel ^{[8
]}

Eibrink, Marry van den Heuvel ^{[9
]}

Heckl, Dirk ^{[1
]}

Fornerod, Maarten ^{[8
]}

Thum, Thomas ^{[1
,11
]}

Humphries, R. Keith ^{[10
]}

Rieger, Michael A. ^{[4
,5
,6
]}

Kuchenbauer, Florian ^{[3
]}

Klusmann, Jan-Henning ^{[2
]}

机构：

[1] Hannover Med Sch, Hannover, Germany

[2] Univ Halle, Halle, Germany

[3] Univ Hosp Ulm, Ulm, Germany

[4] Goethe Univ Frankfurt, Frankfurt, Germany

[5] German Canc Consortium, Heidelberg, Germany

[6] German Canc Res Ctr, Heidelberg, Germany

[7] Univ Hosp Essen, Essen, Germany

[8] Erasmus MC Sophia Childrens Hosp, Rotterdam, Netherlands

[9] Prinses Maxima Ctr Pediat Oncol, Utrecht, Netherlands

[10] Terry Fox Lab, Vancouver, BC, Canada

[11] Imperial Coll London, Natl Heart & Lung Inst, London, England

来源：

JOURNAL OF CLINICAL ONCOLOGY | 2018年 / 36卷 / 10期

基金：

欧洲研究理事会;

关键词：

CELL-PROLIFERATION; SIGNALING PATHWAYS; KINASE CASCADE; LUNG-CANCER; EXPRESSION; DEREGULATION; MIR-193A-3P; ACTIVATION; MIR-139-5P; INHIBITORS;

D O I：

10.1200/JCO.2017.75.2204

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

PurposeDysregulated microRNAs are implicated in the pathogenesis and aggressiveness of acute myeloid leukemia (AML). We describe the effect of the hematopoietic stem-cell self-renewal regulating miR-193b on progression and prognosis of AML.MethodsWe profiled miR-193b-5p/3p expression in cytogenetically and clinically characterized de novo pediatric AML (n = 161) via quantitative real-time polymerase chain reaction and validated our findings in an independent cohort of 187 adult patients. We investigated the tumor suppressive function of miR-193b in human AML blasts, patient-derived xenografts, and miR-193b knockout mice in vitro and in vivo.ResultsmiR-193b exerted important, endogenous, tumor-suppressive functions on the hematopoietic system. miR-193b-3p was downregulated in several cytogenetically defined subgroups of pediatric and adult AML, and low expression served as an independent indicator for poor prognosis in pediatric AML (risk ratio standard error, -0.56 +/- 0.23; P = .016). miR-193b-3p expression improved the prognostic value of the European LeukemiaNet risk-group stratification or a 17-gene leukemic stemness score. In knockout mice, loss of miR-193b cooperated with Hoxa9/Meis1 during leukemogenesis, whereas restoring miR-193b expression impaired leukemic engraftment. Similarly, expression of miR-193b in AML blasts from patients diminished leukemic growth in vitro and in mouse xenografts. Mechanistically, miR-193b induced apoptosis and a G1/S-phase block in various human AML subgroups by targeting multiple factors of the KIT-RAS-RAF-MEK-ERK (MAPK) signaling cascade and the downstream cell cycle regulator CCND1.ConclusionThe tumor-suppressive function is independent of patient age or genetics; therefore, restoring miR-193b would assure high antileukemic efficacy by blocking the entire MAPK signaling cascade while preventing the emergence of resistance mechanisms. (C) 2018 by American Society of Clinical Oncology

引用

页码：1007 / +

页数：11

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