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MicroRNA-708 is a novel regulator of the Hoxa9 program in myeloid cells.
MicroRNA-708 is a novel regulator of the Hoxa9 program in myeloid cells.
- Source :
-
Leukemia [Leukemia] 2020 May; Vol. 34 (5), pp. 1253-1265. Date of Electronic Publication: 2019 Nov 25. - Publication Year :
- 2020
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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.
- Subjects :
- Animals
Apoptosis
CRISPR-Cas Systems
Cell Differentiation
Cell Proliferation
Female
Hematopoiesis
Homeodomain Proteins genetics
Humans
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute metabolism
Mice
Mice, Inbred C57BL
MicroRNAs antagonists & inhibitors
MicroRNAs metabolism
Myeloid Cells metabolism
Myeloid Ecotropic Viral Integration Site 1 Protein genetics
Tumor Cells, Cultured
Gene Expression Regulation, Leukemic
Homeodomain Proteins metabolism
Leukemia, Myeloid, Acute pathology
MicroRNAs genetics
Myeloid Cells pathology
Myeloid Ecotropic Viral Integration Site 1 Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 34
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 31768018
- Full Text :
- https://doi.org/10.1038/s41375-019-0651-1