The balance between the intronic miR-342 and its host gene Evl determines hematopoietic cell fate decision

• Published in: Leukemia Vol. 35; no. 10; pp. 2948 - 2963
• Main Authors: Herbst, Friederike, Lang, Tonio J. L., Eckert, Elias S. P., Wünsche, Peer, Wurm, Alexander A., Kindinger, Tim, Laaber, Karin, Hemmati, Shayda, Hotz-Wagenblatt, Agnes, Zavidij, Oksana, Paruzynski, Anna, Lu, Junyan, von Kalle, Christof, Zenz, Thorsten, Klein, Christoph, Schmidt, Manfred, Ball, Claudia R., Glimm, Hanno
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2021; Nature Publishing Group
• Subjects: 13; 13/100; 13/31; 13/44; 38; 38/77; 42/35; 631/136/232; 631/532/1542; 64/60; 692/308/2171; 82/80; 96/109; Animals; Ataxin; Cancer Research; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Differentiation; Cell fate; Cells (biology); Critical Care Medicine; Differentiation; Expression vectors; Gene mapping; Gene therapy; Genes; Hematology; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Intensive; Internal Medicine; Introns; Leukemia; Loci; Lymphatic leukemia; Lymphocytes B; Lymphopoiesis; Medicine; Medicine & Public Health; Mice; MicroRNAs - genetics; miRNA; Oncology; Peripheral blood; Progenitor cells; Proteins; Germany
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01267-5

Protein-coding and non-coding genes like miRNAs tightly control hematopoietic differentiation programs. Although miRNAs are frequently located within introns of protein-coding genes, the molecular interplay between intronic miRNAs and their host genes is unclear. By genomic integration site mapping of gamma-retroviral vectors in genetically corrected peripheral blood from gene therapy patients, we identified the
EVL/MIR342
gene locus as a hotspot for therapeutic vector insertions indicating its accessibility and expression in human hematopoietic stem and progenitor cells. We therefore asked if and how EVL and its intronic miRNA-342 regulate hematopoiesis. Here we demonstrate that overexpression (OE) of Evl in murine primary Lin
−
Sca1
+
cKit
+
cells drives lymphopoiesis whereas miR-342 OE increases myeloid colony formation in vitro and in vivo, going along with a profound upregulation of canonical pathways essential for B-cell development or myelopoietic functions upon Evl or miR-342 OE, respectively. Strikingly, miR-342 counteracts its host gene by targeting lymphoid signaling pathways, resulting in reduced pre-B-cell output. Moreover, EVL overexpression is associated with lymphoid leukemia in patients. In summary, our data show that one common gene locus regulates distinct hematopoietic differentiation programs depending on the gene product expressed, and that the balance between both may determine hematopoietic cell fate decision.