1. Endogenous tumor suppressor microRNA-193b: Therapeutic and prognostic value in acute myeloid leukemia
- Author
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Bhayadia, R. (Raj), Krowiorz, K. (Kathrin), Haetscher, N. (Nadine), Jammal, R. (Razan), Emmrich, S. (Stephan), Obulkasim, A. (Askar), Fiedler, J. (Jan), Schwarzer, A. (Adrian), Rouhi, A. (Arefeh), Heuser, M. (Michael), Wingert, S. (Susanne), Bothur, S. (Sabrina), Döhner, K. (Konstanze), Mätzig, T. (Tobias), Ng, M. (Michelle), Reinhardt, D. (Dirk), Döhner, H. (Hartmut), Zwaan, C.M. (Michel), Heuvel-Eibrink, M.M. (Marry) van den, Heckl, D. (Dirk), Fornerod, M.W.J. (Maarten), Thum, T. (Thomas), Humphries, R.K. (R. Keith), Rieger, M.A. (Michael A.), Kuchenbauer, F. (Florian), Klusmann, J.-H., Bhayadia, R. (Raj), Krowiorz, K. (Kathrin), Haetscher, N. (Nadine), Jammal, R. (Razan), Emmrich, S. (Stephan), Obulkasim, A. (Askar), Fiedler, J. (Jan), Schwarzer, A. (Adrian), Rouhi, A. (Arefeh), Heuser, M. (Michael), Wingert, S. (Susanne), Bothur, S. (Sabrina), Döhner, K. (Konstanze), Mätzig, T. (Tobias), Ng, M. (Michelle), Reinhardt, D. (Dirk), Döhner, H. (Hartmut), Zwaan, C.M. (Michel), Heuvel-Eibrink, M.M. (Marry) van den, Heckl, D. (Dirk), Fornerod, M.W.J. (Maarten), Thum, T. (Thomas), Humphries, R.K. (R. Keith), Rieger, M.A. (Michael A.), Kuchenbauer, F. (Florian), and Klusmann, J.-H.
- Abstract
Purpose Dysregulated 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. Methods We 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. Results miR-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 6 standard error, 20.56 6 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. Conclusion The 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.
- Published
- 2018
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