1. Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype.
- Author
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Thornton N, Karamatic Crew V, Tilley L, Green CA, Tay CL, Griffiths RE, Singleton BK, Spring F, Walser P, Alattar AG, Jones B, Laundy R, Storry JR, Möller M, Wall L, Charlewood R, Westhoff CM, Lomas-Francis C, Yahalom V, Feick U, Seltsam A, Mayer B, Olsson ML, and Anstee DJ
- Subjects
- Blood Group Antigens chemistry, Blood Group Antigens metabolism, Blood Platelets metabolism, Cells, Cultured, Erythrocyte Membrane metabolism, Erythroid Cells metabolism, Humans, Hyaluronan Receptors metabolism, Membrane Glycoproteins chemistry, Membrane Glycoproteins metabolism, Models, Molecular, Mutation, Phenotype, Protein Binding, Exome Sequencing, Blood Group Antigens genetics, Cell Proliferation, Erythroid Cells cytology, Membrane Glycoproteins genetics
- 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.
- Published
- 2020
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