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Yes, MAM: how the cancer-related EMP3 protein became a regulator of erythropoiesis and the key protein underlying a new blood group system

M.D. Ilsley

M.D. Ilsley

Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund UniversityLund, Sweden
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Ilsley, M.D.
, 
J.R. Storry

J.R. Storry

Experimental Transfusion Medicine, Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Technical Director, Immunohematology, Department of Clinical Immunology and Transfusion Medicine, Office of Medical ServicesLund,
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Storry, J.R.
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M.L. Olsson

M.L. Olsson

Transfusion Medicine, Deputy Dean, Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Medical Director of the Nordic Reference Laboratory for Genomic Blood Group Typing, Department of Clinical Immunology and Transfusion Medicine, Office of Medical ServicesLund,
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Olsson, M.L.
  
Dec 28, 2022
Yes, MAM: how the cancer-related EMP3 protein became a regulator of erythropoiesis and the key protein underlying a new blood group system's Cover Image
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Published Online: Dec 28, 2022
Page range: 130 - 136
DOI: https://doi.org/10.21307/immunohematology-2022-055
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© 2022 M.D. Ilsley et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Fig. 1

(A) Schematic of EMP3 structure. Transmembrane domains are symbolized by colored circles. Confirmed N-glycan site (N47) is indicated (image created in BioRender.com). (B) Ribbon diagram of EMP3 extracellular domain. Cysteines believed to form a disulfide bond (C54 and C43) are indicated (generated by Alphafold2).
(A) Schematic of EMP3 structure. Transmembrane domains are symbolized by colored circles. Confirmed N-glycan site (N47) is indicated (image created in BioRender.com). (B) Ribbon diagram of EMP3 extracellular domain. Cysteines believed to form a disulfide bond (C54 and C43) are indicated (generated by Alphafold2).

Fig. 2

(A) Timeline and description of the three phases of erythroid CD34+ progenitor cell culture. HSPC = hematopoietic stem and progenitor cells. (B) Cell culture of CD34+ cells from an EMP– individual (MAM_NEG) compared with two EMP+ control subjects (C1 and C2). EMP3– cells show a significantly increased growth during the expansion phase and a greater number of cells at the end of culture. ns = not significant; ****p < 0.0001. (Figure courtesy of Dr. A.G. Alattar, who performed the original experiment.)
(A) Timeline and description of the three phases of erythroid CD34+ progenitor cell culture. HSPC = hematopoietic stem and progenitor cells. (B) Cell culture of CD34+ cells from an EMP– individual (MAM_NEG) compared with two EMP+ control subjects (C1 and C2). EMP3– cells show a significantly increased growth during the expansion phase and a greater number of cells at the end of culture. ns = not significant; ****p < 0.0001. (Figure courtesy of Dr. A.G. Alattar, who performed the original experiment.)

Fig. 3

Examples of Kaplan-Meier plots showing the influence of EMP3 expression on survival probability of patients with various cancers (data from https://www.proteinatlas.org/ENSG00000142227-EMP3, accessed on 5 August 2022). For renal and stomach cancers, EMP3 expression has been determined to be prognostic by the Human Protein Atlas with data from The Cancer Genome Atlas.
Examples of Kaplan-Meier plots showing the influence of EMP3 expression on survival probability of patients with various cancers (data from https://www.proteinatlas.org/ENSG00000142227-EMP3, accessed on 5 August 2022). For renal and stomach cancers, EMP3 expression has been determined to be prognostic by the Human Protein Atlas with data from The Cancer Genome Atlas.

Molecular basis of the MAM- phenotype

Allele name Nucleotide change Exon Amino acid change Reference rs number Identified in (n) gnomAD† frequency of the variant allele (≥0.01%)
MAM*01N.01 c.123>G 3 p.Tyr41Ter rs201392469 0.003 Middle East
c.373A>G 5 p.lle125Val Thornton et al.5 rs4893 Middle East region (3) 0.002 Ashkenazi Jew0.041 European and Middle East
MAM*01N.02 c.182-186_322+418del (745bp deletion) 4 p.Trp62_Ser108del Thornton et al.5 NA Turkish (2) ND
MAM*01N.03 c.323-231_492+338del (822bp deletion) 5 p.Val109_Ter164del Thornton et al.5 NA Not known (1 ; Germany) ND
MAM*01N.04 c.1-3513_492+1379del (8518bp deletion) 1–5 p.Met1_Ter164del Thornton et al.5 NA White/Cherokee (1; United States) ND
MAM*01N.05 c.1-3532_492+1361del (8519bp deletion) 1–5 p.Met1_Ter164del Thornton et al.5 NA White (1; New Zealand) ND
Not yet assigned c.341 to IVS5+688 (923bp) 5 p.Gly114_Ter164del Baglow et al.7 NA Malaysian (1) ND
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