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MicroRNA-708 is a novel regulator of the Hoxa9 program in myeloid cells.

Journal article
Authors Edith Schneider
Nicole Pochert
Christoph Ruess
Liam MacPhee
Leo Escano
Christina Miller
Kathrin Krowiorz
Erik Delsing Malmberg
Alireza Heravi-Moussavi
Alireza Lorzadeh
Arghavan Ashouri
Sarah Grasedieck
Nadine Sperb
Pradeep Kumar Kopparapu
Sebastian Iben
Anna Staffas
Ping Xiang
Reinhild Rösler
Meena Kanduri
Erik Larsson
Linda Fogelstrand
Hartmut Döhner
Konstanze Döhner
Sebastian Wiese
Martin Hirst
R Keith Humphries
Lars Palmqvist
Florian Kuchenbauer
Arefeh Rouhi
Published in Leukemia
ISSN 1476-5551
Publication year 2019
Published at Institute of Biomedicine
Institute of Medicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Language en
Links dx.doi.org/10.1038/s41375-019-0651-...
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Cancer and Oncology, Hematology

Abstract

MicroRNAs (miRNAs) are commonly deregulated in acute myeloid leukemia (AML), affecting critical genes not only through direct targeting, but also through modulation of downstream effectors. Homeobox (Hox) genes balance self-renewal, proliferation, cell death, and differentiation in many tissues and aberrant Hox gene expression can create a predisposition to leukemogenesis in hematopoietic cells. However, possible linkages between the regulatory pathways of Hox genes and miRNAs are not yet fully resolved. We identified miR-708 to be upregulated in Hoxa9/Meis1 AML inducing cell lines as well as in AML patients. We further showed Meis1 directly targeting miR-708 and modulating its expression through epigenetic transcriptional regulation. CRISPR/Cas9 mediated knockout of miR-708 in Hoxa9/Meis1 cells delayed disease onset in vivo, demonstrating for the first time a pro-leukemic contribution of miR-708 in this context. Overexpression of miR-708 however strongly impeded Hoxa9 mediated transformation and homing capacity in vivo through modulation of adhesion factors and induction of myeloid differentiation. Taken together, we reveal miR-708, a putative tumor suppressor miRNA and direct target of Meis1, as a potent antagonist of the Hoxa9 phenotype but an effector of transformation in Hoxa9/Meis1. This unexpected finding highlights the yet unexplored role of miRNAs as indirect regulators of the Hox program during normal and aberrant hematopoiesis.

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