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

Nicole Thornton (), Vanja Karamatic Crew, Louise Tilley, Carole A. Green, Chwen Ling Tay, Rebecca E. Griffiths, Belinda K. Singleton, Frances Spring, Piers Walser, Abdul Ghani Alattar, Benjamin Jones, Rosalind Laundy, Jill R. Storry, Mattias Möller, Lorna Wall, Richard Charlewood, Connie M. Westhoff, Christine Lomas-Francis, Vered Yahalom, Ute Feick, Axel Seltsam, Beate Mayer, Martin L. Olsson and David J. Anstee
Additional contact information
Nicole Thornton: International Blood Group Reference Laboratory, NHS Blood and Transplant
Vanja Karamatic Crew: International Blood Group Reference Laboratory, NHS Blood and Transplant
Louise Tilley: International Blood Group Reference Laboratory, NHS Blood and Transplant
Carole A. Green: Bristol Institute for Transfusion Sciences, NHS Blood and Transplant and NIHR Blood and Transplant Unit in Red Cell Products, University of Bristol
Chwen Ling Tay: International Blood Group Reference Laboratory, NHS Blood and Transplant
Rebecca E. Griffiths: Bristol Institute for Transfusion Sciences, NHS Blood and Transplant and NIHR Blood and Transplant Unit in Red Cell Products, University of Bristol
Belinda K. Singleton: Bristol Institute for Transfusion Sciences, NHS Blood and Transplant and NIHR Blood and Transplant Unit in Red Cell Products, University of Bristol
Frances Spring: Bristol Institute for Transfusion Sciences, NHS Blood and Transplant and NIHR Blood and Transplant Unit in Red Cell Products, University of Bristol
Piers Walser: International Blood Group Reference Laboratory, NHS Blood and Transplant
Abdul Ghani Alattar: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University
Benjamin Jones: International Blood Group Reference Laboratory, NHS Blood and Transplant
Rosalind Laundy: International Blood Group Reference Laboratory, NHS Blood and Transplant
Jill R. Storry: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University
Mattias Möller: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University
Lorna Wall: Reference Laboratory, New Zealand Blood Service
Richard Charlewood: Reference Laboratory, New Zealand Blood Service
Connie M. Westhoff: New York Blood Centre
Christine Lomas-Francis: New York Blood Centre
Vered Yahalom: Magen David Adom, National Blood Services
Ute Feick: Deutsches Rotes Kreuz, Blood Donor Service, Institute Bad Kreuznach
Axel Seltsam: German Red Cross Blood Service NSTOB, Institute Springe
Beate Mayer: Institute of Transfusion Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health
Martin L. Olsson: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University
David J. Anstee: Bristol Institute for Transfusion Sciences, NHS Blood and Transplant and NIHR Blood and Transplant Unit in Red Cell Products, University of Bristol

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17060-4

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