Page 46 - Haematologica3

Correspondence:
dnyu@yzu.edu.cn
Received: July 27, 2017.
Accepted: December 20, 2017. Pre-published: December 21, 2017.
doi:10.3324/haematol.2017.177394
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/3/406
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Haematologica 2018 Volume 103(3):406-416
1Clinical Medical College of Yangzhou University, Yangzhou, China; 2Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, University School of Medicine, China; 3Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA; 4Department of Pediatrics, Jingjiang People’s Hospital, Yangzhou University, Jingjiang, China; 5Institute of Comparative Medicine, Yangzhou University, China; 6Institute of Translational Medicine, Yangzhou University School of Medicine, Yangzhou, China and 7Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou, China
Ferrata Storti Foundation
Red Cell Biology & Its Disorders
miR-144/451 represses the LKB1/AMPK/mTOR pathway to promote red cell precursor survival during recovery from acute anemia
Xiao Fang,1,2,* Feiyang Shen,2,* Christophe Lechauve,3 Peng Xu,3 Guowei Zhao,3 Jacobi Itkow,2 Fan Wu,2 Yaying Hou,2 Xiaohui Wu,2,4 Lingling Yu,2,4 Huiqing Xiu,2 Mengli Wang,2 Ruiling Zhang,2 Fangfang Wang,2 Yanqing Zhang,2 Daxin Wang,1 Mitchell J. Weiss3 and Duonan Yu2,5,6,7
*XF and FS contributed equally to this work. ABSTRACT
The microRNAs miR-144 and -451 are encoded by a bicistronic gene that is strongly induced during red blood cell formation (erythro- poiesis). Ablation of the miR-144/451 gene in mice causes mild anemia under baseline conditions. Here we show that miR-144/451-/- ery- throblasts exhibit increased apoptosis during recovery from acute ane- mia. Mechanistically, miR-144/451 depletion increases the expression of the miR-451 target mRNA Cab39, which encodes a co-factor for the ser- ine-threonine kinase LKB1. During erythropoietic stress, miR-144/451-/- erythroblasts exhibit abnormally increased Cab39 protein, which acti- vates LKB1 and its downstream AMPK/mTOR effector pathway. Suppression of this pathway via drugs or shRNAs enhances survival of the mutant erythroblasts. Thus, miR-144/451 facilitates recovery from acute anemia by repressing Cab39/AMPK/mTOR. Our findings suggest that miR-144/451 is a key protector of erythroblasts during pathological states associated with dramatically increased erythropoietic demand, including acute blood loss and hemolytic anemia.
Introduction
Dysregulation of microRNAs (miRNAs) is implicated in the pathophysiology of many human diseases including cancer, cardiovascular disease, and anemia.1,2 There is increasing evidence that miRNAs regulate red blood cell (RBC) formation (erythropoiesis) by controlling the proliferation and differentiation of RBC precur- sors, termed erythroblasts.3 For example, miR-126 negatively regulates erythro- poiesis by repressing mRNA encoding the tyrosine phosphatase PTPN9, which is required for erythroblast proliferation,4 whereas ectopic expression of miR-27a, miR-24, and miR-146b in CD34+ hematopoietic progenitor cells promotes erythroid maturation by repressing GATA-2 or increasing GATA-1, which activates the GATA switch, a key step in erythropoiesis.5,6 However, the role of miRNAs and their targets in regulating erythropoiesis is not fully understood.
The bicistronic miRNA locus encoding miRs-144 and -451 is strongly induced during erythropoiesis in zebrafish, mice, and humans.7-9 Chromatin immunoprecip- itation (ChIP) and gene complementation studies show that miR-144/451 transcrip- tion is activated by GATA-1,10 a transcription factor that regulates many aspects of erythropoiesis, including precursor proliferation, maturation, and survival. Remarkably, miR-451 accounts for approximately 50% of the total miRNA pool in mouse fetal liver (FL) erythroblasts.11 Unlike most miRNAs, miR-451 biogenesis occurs independently of the RNA III enzyme Dicer. Rather, it is Argonaut 2 (Ago2)
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