miR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding

Leukemia
Danyue PengLingbo Liu

Abstract

Leukemia stem cells (LSCs) are responsible for acute myeloid leukemia (AML) chemotherapy resistance and relapse. Here, we discovered that miR-34c-5p, a microRNA central to the senescence regulation network, was significantly down-regulated in AML (non-acute promyelocytic leukemia, non-APL) stem cells compared to that in normal hematopoietic stem cells (HSCs). The lower expression of miR-34c-5p in LSCs was closely correlated to the adverse prognosis and poor responses to therapy of AML patients. Increased miR-34c-5p expression induced LSCs senescence ex vivo, prevented leukemia development and promoted the eradication of LSCs in immune deficient mice. Mechanistically, forced expression of miR-34-5p induced senescence in LSCs through p53-p21Cip1-Cyclin-dependent kinase (CDK)/Cyclin or p53-independent CDK/Cyclin pathways. Exosome-mediated transfer of miR-34c-5p was one of the reasons for miR-34c-5p deficiency in LSCs. Furthermore, miR-34c-5p could increase its intracellular level by inhibiting exosome-mediated transfer via a positive feedback loop through RAB27B, a molecule that promotes exosome shedding. Overall, this study establishes a new strategy for treatment of AML patients by targeting LSCs to reinitiate senescence via inc...Continue Reading

References

Aug 29, 2006·Oncogene·C Giacinti, A Giordano
Jul 31, 2007·Cell·Manuel ColladoManuel Serrano
Aug 2, 2007·Nature Reviews. Molecular Cell Biology·Judith Campisi, Fabrizio d'Adda di Fagagna
Dec 7, 2007·Cancer Research·Xingyue HeGregory J Hannon
Mar 1, 2008·Science·Katarina TrajkovicMikael Simons
Sep 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Amaia LujambioManel Esteller
May 23, 2009·Cell Death and Differentiation·H Hermeking
Jul 16, 2009·Nature Reviews. Molecular Cell Biology·Harald Stenmark
Dec 23, 2009·Nature Cell Biology·Suzanne R Pfeffer
Mar 4, 2010·International Journal of Molecular Medicine·Ke-Min CaiXiao-Jun Zhao
Mar 31, 2010·Biochemical and Biophysical Research Communications·Dominik FuchsCord Naujokat
Dec 16, 2010·The Journal of Clinical Investigation·Jean-Emmanuel SarryMartin Carroll
Feb 26, 2011·International Journal of Cancer. Journal International Du Cancer·Zandra HagmanYvonne Ceder
Aug 30, 2011·Nature Medicine·Kolja EppertJohn E Dick
May 16, 2012·Cancer Discovery·Barbara BenassiMassimo Loda
Jun 12, 2012·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Yin XiaoLingbo Liu
Aug 11, 2012·Journal of the National Comprehensive Cancer Network : JNCCN·Margaret R O'DonnellKristina M Gregory
Feb 19, 2013·Oncogene·A RufiniG Melino
Aug 8, 2013·British Journal of Cancer·Z HagmanY Ceder
Aug 29, 2013·International Journal of Biological Sciences·Bing-rong ZhouDan Luo
Nov 14, 2013·Journal of Extracellular Vesicles·Rossella CrescitelliJan Lötvall
Jan 23, 2014·Genes & Development·Rafik SalamaMasashi Narita
Jan 1, 2012·Longevity & Healthspan·Elisabeth Schraml, Johannes Grillari
Feb 20, 2014·Frontiers in Molecular Neuroscience·Shephali BhatnagarEugenia Wang
May 13, 2014·Journal of Molecular Cell Biology·Matjaz RokavecHeiko Hermeking
Aug 1, 2015·Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban·Dan-Yue PengLing-Bo Liu
May 3, 2016·Leukemia·Y ZhengT Cheng

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Citations

Aug 27, 2019·Artificial Cells, Nanomedicine, and Biotechnology·Yuqiang WangYaJun Miao
Dec 6, 2018·Journal of Cellular Physiology·Rajab MardaniHossein Pourghadamyari
Apr 10, 2019·Neuromolecular Medicine·Abhishek Jauhari, Sanjay Yadav
Aug 28, 2019·Journal of Cellular Biochemistry·Jiarui Liu, Xin Wang
Apr 24, 2020·Frontiers in Immunology·Yanyan TangQianjin Liao
Apr 8, 2020·Cells·Hyunwoo KimBuHyun Youn
Feb 6, 2019·Journal of Experimental & Clinical Cancer Research : CR·Lu ZhangLiling Tang
May 28, 2019·Journal of Hematology & Oncology·Yan LiuLin Fu
Apr 2, 2020·The Journal of International Medical Research·Lin-Zhu YangXi Zhan
Nov 18, 2019·Critical Reviews in Oncology/hematology·Mara FernandesRui Medeiros
Jan 8, 2021·Cancer Management and Research·Chenxi LiaoLingbo Liu
Mar 9, 2021·Signal Transduction and Targeted Therapy·Chaoyue SuLiwu Fu
Apr 4, 2021·Genes·Dorian ForteLucia Catani
Jun 19, 2021·Frontiers in Cell and Developmental Biology·Hongyuan JinHangyu Li
Jul 23, 2021·Cell Biology International·Maedeh MasoumipourSeyed Hadi Mousavi

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Methods Mentioned

BETA
Assay
flow cytometry
transfection
flow

Software Mentioned

rna22
GraphPad Prism
GraphPad

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