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

共 48 条

[1] Predicting effective microRNA target sites in mammalian mRNAs [J].

Agarwal, Vikram ;

Bell, George W. ;

Nam, Jin-Wu ;

Bartel, David P. .

ELIFE, 2015, 4

[2] MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road [J].

Caunt, Christopher J. ;

Sale, Matthew J. ;

Smith, Paul D. ;

Cook, Simon J. .

NATURE REVIEWS CANCER, 2015, 15 (10) :577-592

[3] Drugging the undruggable RAS: Mission Possible? [J].

Cox, Adrienne D. ;

Fesik, Stephen W. ;

Kimmelman, Alec C. ;

Luo, Ji ;

Der, Channing J. .

NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (11) :828-851

[4] First experience of the AML-Berlin-Frankfurt-Munster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoid acid [J].

Creutzig, Ursula ;

Dworzak, Michael N. ;

Bochennek, Konrad ;

Faber, Joerg ;

Flotho, Christian ;

Graf, Norbert ;

Kontny, Udo ;

Rossig, Claudia ;

Schmid, Irene ;

von Stackelberg, Arend ;

Mueller, Jans-Enno ;

von Neuhoff, Christine ;

Reinhardt, Dirk ;

von Neuhoff, Nils .

PEDIATRIC BLOOD & CANCER, 2017, 64 (08)

[5] Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel [J].

Creutzig, Ursula ;

van den Heuvel-Eibrink, Marry M. ;

Gibson, Brenda ;

Dworzak, Michael N. ;

Adachi, Souichi ;

de Bont, Eveline ;

Harbott, Jochen ;

Hasle, Henrik ;

Johnston, Donna ;

Kinoshita, Akitoshi ;

Lehrnbecher, Thomas ;

Leverger, Guy ;

Mejstrikova, Ester ;

Meshinchi, Soheil ;

Pession, Andrea ;

Raimondi, Susana C. ;

Sung, Lillian ;

Stary, Jan ;

Zwaan, Christian M. ;

Kaspers, Gertjan J. L. ;

Reinhardt, Dirk .

BLOOD, 2012, 120 (16) :3187-3205

[6] MRX34, a liposomal miR-34 mimic and potential firstin-class microRNA therapeutic: activity in animal models of liver cancer [J].

Daige, Chris ;

Priddy, Leslie ;

Wiggins, Jason ;

Nelligan-Davis, Terri ;

Enzler, Danlee ;

Vadnagara, Komal ;

Brown, David .

JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (15)

[7] miR-139-5p controls translation in myeloid leukemia through EIF4G2 [J].

Emmrich, S. ;

Engeland, F. ;

El-Khatib, M. ;

Henke, K. ;

Obulkasim, A. ;

Schoening, J. ;

Katsman-Kuipers, J. E. ;

Zwaan, C. Michel ;

Pich, A. ;

Stary, J. ;

Baruchel, A. ;

de Haas, V. ;

Reinhardt, D. ;

Fornerod, M. ;

van den Heuvel-Eibrink, M. M. ;

Klusmann, J. H. .

ONCOGENE, 2016, 35 (14) :1822-1831

[8] miR-9 is a tumor suppressor in pediatric AML with t(8;21) [J].

Emmrich, S. ;

Katsman-Kuipers, J. E. ;

Henke, K. ;

Khatib, M. E. ;

Jammal, R. ;

Engeland, F. ;

Dasci, F. ;

Zwaan, C. M. ;

den Boer, M. L. ;

Verboon, L. ;

Stary, J. ;

Baruchel, A. ;

de Haas, V. ;

Danen-van Oorschot, A. A. ;

Fornerod, M. ;

Pieters, R. ;

Reinhardt, D. ;

Klusmann, J. H. ;

van den Heuvel-Eibrink, M. M. .

LEUKEMIA, 2014, 28 (05) :1022-1032

[9] miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling [J].

Emmrich, Stephan ;

Rasche, Mareike ;

Schoening, Jennifer ;

Reimer, Christina ;

Keihani, Sarva ;

Maroz, Aliaksandra ;

Xie, Ying ;

Li, Zhe ;

Schambach, Axel ;

Reinhardt, Dirk ;

Klusmann, Jan-Henning .

GENES & DEVELOPMENT, 2014, 28 (08) :858-874

[10] Multifunctional Aptamer-miRNA Conjugates for Targeted Cancer Therapy [J].

Esposito, Carla L. ;

Cerchia, Laura ;

Catuogno, Silvia ;

De Vita, Gennaro ;

Dassie, Justin P. ;

Santamaria, Gianluca ;

Swiderski, Piotr ;

Condorelli, Gerolama ;

Giangrande, Paloma H. ;

de Franciscis, Vittorio .

MOLECULAR THERAPY, 2014, 22 (06) :1151-1163

← 1 2 3 4 5 →