Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype
Open Access
- 16 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-11
- https://doi.org/10.1038/s41467-020-17060-4
Abstract
The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. Its molecular basis is unknown. By whole-exome sequencing we identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, then demonstrate inactivating mutations in ten known MAM-negative individuals. We show that EMP3, a purported tumour suppressor in various solid tumours, is expressed in erythroid cells. Disruption of EMP3 by CRISPR/Cas9 gene editing in an immortalised human erythroid cell line (BEL-A2) abolishes MAM expression. We find EMP3 to associate with, and stabilise, CD44 in the plasma membrane. Furthermore, cultured erythroid progenitor cells from MAM-negative individuals show markedly increased proliferation and higher reticulocyte yields, suggesting an important regulatory role for EMP3 in erythropoiesis and control of cell production. Our data establish MAM as a new blood group system and demonstrate an interaction of EMP3 with the cell surface signalling molecule CD44.Funding Information
- Knut och Alice Wallenbergs Stiftelse (2014.0312)
- Swedish governmental ALF grants
- DH | National Institute for Health Research (NIHR-BTRU-2015-10032)
This publication has 33 references indexed in Scilit:
- RNA-Guided Human Genome Engineering via Cas9Science, 2013
- Multiplex Genome Engineering Using CRISPR/Cas SystemsScience, 2013
- Maturing reticulocytes internalize plasma membrane in glycophorin A–containing vesicles that fuse with autophagosomes before exocytosisBlood, 2012
- Integrative Genomics Viewer (IGV): high-performance genomics data visualization and explorationBriefings in Bioinformatics, 2012
- ABCB6 is dispensable for erythropoiesis and specifies the new blood group system LangereisNature Genetics, 2012
- HIF1α synergizes with glucocorticoids to promote BFU-E progenitor self-renewalBlood, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesisProceedings of the National Academy of Sciences of the United States of America, 2009
- CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skinBlood, 2004
- Evidence That the Human Blood Group Antigens Gyaand Hy Are Carried on a Novel Glycosylphosphatidylinositol-Linked Erythrocyte Membrane GlycoproteinVox Sanguinis, 1991