title: Overexpression and knockout of miR-126 both promote leukemogenesis.
abstract: It is generally assumed that gain- and loss-of-function manipulations of a functionally important gene should lead to the opposite phenotypes. We show in this study that both overexpression and knockout of microRNA (miR)-126 surprisingly result in enhanced leukemogenesis in cooperation with the t(8;21) fusion genes AML1-ETO/RUNX1-RUNX1T1 and AML1-ETO9a (a potent oncogenic isoform of AML1-ETO). In accordance with our observation that increased expression of miR-126 is associated with unfavorable survival in patients with t(8;21) acute myeloid leukemia (AML), we show that miR-126 overexpression exhibits a stronger effect on long-term survival and progression of AML1-ETO9a-mediated leukemia stem cells/leukemia initiating cells (LSCs/LICs) in mice than does miR-126 knockout. Furthermore, miR-126 knockout substantially enhances responsiveness of leukemia cells to standard chemotherapy. Mechanistically, miR-126 overexpression activates genes that are highly expressed in LSCs/LICs and/or primitive hematopoietic stem/progenitor cells, likely through targeting ERRFI1 and SPRED1, whereas miR-126 knockout activates genes that are highly expressed in committed, more differentiated hematopoietic progenitor cells, presumably through inducing FZD7 expression. Our data demonstrate that miR-126 plays a critical but 2-faceted role in leukemia and thereby uncover a new layer of miRNA regulation in cancer. Moreover, because miR-126 depletion can sensitize AML cells to standard chemotherapy, our data also suggest that miR-126 represents a promising therapeutic target.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH;
authors.forename: Rui
authors.initials: R
authors.lastname: Su
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH; Institute of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, People's Republic of China;
authors.forename: Chao
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH; Institute of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, People's Republic of China;
authors.forename: Yungui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL; Department of Pharmacology, China Medical University, Shenyang, Liaoning, China;
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL;
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH;
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Translational and Functional Genomics Branch and Microarray Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Shenglai
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH;
authors.forename: Hengyou
authors.initials: H
authors.lastname: Weng
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX; Department of Cell and Molecular Biology, Tulane University, New Orleans, LA; and.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX;
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL;
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH;
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, China Medical University, Shenyang, Liaoning, China;
authors.forename: Minjie
authors.initials: M
authors.lastname: Wei
authors.affiliation: Institute of Hematology, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, People's Republic of China;
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: Translational and Functional Genomics Branch and Microarray Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Paul P
authors.initials: PP
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH;
authors.forename: Jianjun
authors.identifier: http://orcid.org/0000-0003-3749-2902
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D015996:Survival Rate; D014178:Translocation, Genetic / Q000235:genetics
chemical_list: C527111:MIRN126 microRNA, human; C545201:MIRN126 microRNA, mouse; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion