Another step in understanding the ABO and FORS blood group systems
The new paper published by the Immunohematology and Glycobiology Group describes why FORS-1 negative people have FORS-1 positive cancers
We are all familiar with the blood groups A, B, AB and O, which are so important when somebody needs a blood transfusion. Most of us also know that tags on the outside of cells called antigens are what label the individual red blood cells (RBCs); A antigen for type A RBCs, B antigen for type B, both A and B antigens for type AB, and no A or B antigen for type O. What is less commonly known is the simple genetics and biochemistry behind this system. The A and B antigens are produced, respectively, by the actions of enzymes called A and B transferases encoded by the functional A and B genes at the ABO genetic locus. In other words, type A individuals have one or two A gene(s) encoding A transferase that synthesizes A antigen. Type B individuals have one or two B gene(s) encoding B transferase that synthesizes B antigen. Similarly, type AB individuals have both A and B genes (one from father and the other from mother), and express both A and B transferases and synthesize both A and B antigens. However, type O individuals have neither A nor B genes, and as a result neither A nor B antigens are produced. Type O individuals instead have two O genes (one each form father and mother).
In 1990, Dr. Yamamoto’s research group cloned the human A, B, and O genes, and demonstrated the differences between A, B, and O genes in the genetic information (DNA). They also showed how different enzymes of A and B transferases are produced based on the genetic information. Those fundamental discoveries are now widely mentioned in some of the college-level textbooks of genetics, biochemistry, transfusion and transplantation medicines, and even forensic sciences or evolution studies.
ABO is not the only blood group system, and there are 36 systems known to date. However, less is known about the other systems. It should also be noted that many of the blood group antigens are not restricted to RBCs, but they are also expressed on other types of cells. In case of A and B antigens, depending on the ABO type, these antigens are also present on many of the epithelial cells of gastrointestinal tract and endothelial cells lining blood capillaries, which is why ABO matching is critical not only for blood transfusion but also the transplantation of cells, tissues and organs. They may also be expressed on proteins in secretion. Because of these, the ABO typing has been useful of the biological specimens (blood, skin, saliva, seminal fluid, etc.) found in the crime scene investigation.
Dr. Yamamoto’s group is currently working on the Forssman (FORS) blood group system because although most humans cannot produce the Forssman antigen (FORS1), it is found in cancer cells and tissues. Understanding its role and how it is produced will unlock another secret of this disease and give doctors more ways to diagnose and combat it.
In this paper, published in the new on-line journal of the American Society of Hematology (ASH), Miyako Yamamoto, Emili Cid, and Fumiichiro Yamamoto of the Immunohematology and Glycobiology group have defined a molecular mechanism by which cells of people who do not usually have the FORS1 antigen start making the antigen in cancer. As opposed to the prediction that genetic and/or epigenetic activation of the GBGT1 gene, which encodes non-functional enzyme and cannot synthesize the FORS1 antigen, might be responsible for the appearance of FORS1 antigen, they have found that alterations in mRNA splicing of blood group A gene, and not the GBGT1 gene, produced functional enzyme. Because alterations in mRNA splicing are a hallmark of cancer, and many genes are already known to undergo splicing alterations during carcinogenesis, this mechanism may explain why FORS1 negative people have FORS1 positive cancers.
Miyako Yamamoto explains, “Blood groups are very complex, but understanding more about them is vital, not only for blood transfusions and transplants, but also for diagnosing and treating malignant diseases including blood cancer. Our work consists of many small and very difficult steps, but we are very happy to be contributing to this important area of knowledge in blood biology”.
Blood Adv 26 Dec 2017, 1 (27) 2756-2766. Epub 20 Dec 2017
ABO blood group A transferases catalyze the biosynthesis of FORS blood group FORS1 antigen upon deletion of exon 3 or 4.
Yamamoto M, Cid E, Yamamoto F