Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype

• Published in: Nature communications 2020-07, Vol.11 (1), p.3569-3569, Article 3569
• Main Authors: Thornton, Nicole, Karamatic Crew, Vanja, Tilley, Louise, Green, Carole A., Tay, Chwen Ling, Griffiths, Rebecca E., Singleton, Belinda K., Spring, Frances, Walser, Piers, Alattar, Abdul Ghani, Jones, Benjamin, Laundy, Rosalind, Storry, Jill R., Möller, Mattias, Wall, Lorna, Charlewood, Richard, Westhoff, Connie M., Lomas-Francis, Christine, Yahalom, Vered, Feick, Ute, Seltsam, Axel, Mayer, Beate, Olsson, Martin L., Anstee, David J.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/109; 13/31; 14; 14/1; 14/19; 38; 45; 45/22; 45/23; 45/77; 631/208/514/1948; 631/250/232/1473; 692/308/2056; Antigens; Blood Group Antigens - chemistry; Blood Group Antigens - genetics; Blood Group Antigens - metabolism; Blood groups; Blood Platelets - metabolism; CD44 antigen; Cell Proliferation; Cell surface; Cells, Cultured; Clinical Medicine; CRISPR; Disruption; Erythrocyte Membrane - metabolism; Erythroid cells; Erythroid Cells - cytology; Erythroid Cells - metabolism; Erythropoiesis; Exome Sequencing; Genetic modification; Genome editing; Hematologi; Hematology; Humanities and Social Sciences; Humans; Hyaluronan Receptors - metabolism; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Membrane Glycoproteins - chemistry; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane proteins; Membranes; Models, Molecular; multidisciplinary; Mutation; Phenotype; Phenotypes; Progenitor cells; Protein Binding; Reticulocytes; Science; Science (multidisciplinary); Signaling; Solid tumors; Stem cells; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17060-4

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. The molecular basis of the clinically important MAM blood group antigen present in most humans is unknown. We identify EMP3 as its encoding gene, establishing MAM as a new blood group system, and demonstrate the role of EMP3 in erythropoiesis through its interaction with the signalling molecule CD44.