Immunohematology and Glycobiology

Campus ICO-Germans Trias i Pujol

Josep Carreras Leukaemia Research Institute
Edifici IMPPC
Can Ruti Campus, Ctra de Can Ruti
Camí de les Escoles s/n
08916 Badalona, Barcelona, Spain

Laboratory 2-7 (second floor) Office 2-8

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Summary

Blood group ABO system consists of A and B oligosaccharide antigens and the antibodies against those antigens (anti-A and anti-B antibodies, respectively). Matching of ABO blood groups is fundamental for safe blood transfusion. Because A and B antigens may also be expressed on other types of cells than red blood cells, the ABO matching is also important in the transplantation of cells/tissues/organs. Starting from the cloning of the human blood group ABO genes and the elucidation of the allelic basis of the ABO system, we have been investigating ABO genes, the gene-encoded A and B glycosyltransferases, and A and B oligosaccharide antigens, their enzymatic reaction products. We have contributed to science and medicine in a variety of research fields such as molecular genetics, human genetics, population genetics, genotyping, enzymology, biochemistry, glycobiology, hematology, immunology, cellular and developmental biology, forensic science, cancer research, and even in the study of evolution.

Research

We have the following lines of research in progress or under development.

  • ABO polymorphism alters the susceptibility to cardiovascular diseases (venous thromboembolism, coronary artery disease, coagulation disease), infectious diseases (brain malaria caused byPlasmodium falciparum, stomach ulcer by Helicobacter pylori, viral gastroenteritis by Noroviruses), and cancer (pancreatic and gastric cancers).

We are interested in the molecular mechanisms conferring this differential disease susceptibility.

  • The ABO family of genes (ABO, GBGT1, A3GALT2, GGTA1, and GLT6D1) has evolved through gene duplications followed by divergence. In addition to the acquisition of different enzymatic activity and specificity by the gene-encoded glycosyltransferases, the genes may have suffered translocation, recombination, and additional genetic/epigenetic changes.

We would like to delineate the processes that might have occurred during the evolution of the ABO family of genes.

  • Cell-surface glycosylation patterns, also known as glycoprofiles, change during proliferation and differentiation of cells, including the hematopoietic stem cells, which produce a variety of cell types present in blood and lymph. The glycoprofile is radically altered after cells are transformed to become cancerous. Being exposed on cell surface and occasionally excreted into blood and lymph, cancer-specific glycoepitopes can serve as the targets of medical intervention as well as the markers for non-invasive diagnosis and monitoring of cancer.

We anticipate that cells exhibiting different glycoprofiles may possess differential susceptibility to certain chemotherapeutic drugs. We will FACS sort leukemic cell line cells/clinical specimens of leukemic cells into populations exhibiting different glycoprofiles, and examine their drug sensitivity. Because several stem-cell markers are already known to be glycoepitopes, this may allow the identification of medications that are specific to cancer cells with stem cell properties.

  • Our research group has recently developed a method to customize cells exhibiting certain glycolipids by the introduction of retroviral vectors to express a selected set of glycosyltransferases into cells having only the core structure of glycolipid. 

We have been utilizing this method to create cells with cancer-specific glycoepitopes, which will soon be used to screen a human single chain (scFv) antibody library and to identify monoclonal single chain antibodies that are reactive to the selected cancer-specific glycoepitopes. Those antibodies may have a potential to be modified to molecularly target leukemic cells for immunotherapy such as adoptive transfer of T cells expressing chimeric antigen receptor against those epitopes.

For more information on the molecular genetic basis of the ABO blood group system, please see the following pages.

English site (http://sites.google.com/site/abobloodgroup/)
Catalan site (https://sites.google.com/site/grupsanguiniaboab0/)
Spanish site (http://sites.google.com/site/gruposanguineoab0/home)
Japanese site (http://sites.google.com/site/abobloodgroup/home2)

Awards

  • Docteur honoris causa de Republique francaise (Dr. h.c) from L’Universite de Toulouse III (Universite Paul Sabatier), France (2011)
  • Wako Lecture, Japanese Society of Blood Transfusion & Cell Therapy, (co-organized with the ISBT (2009).
  • Chaire d’Excellence, Pierre de Fermat Honorary Lecture at the Pierre de Fermat Symposium on Molecular Genetic Bases of Blood Group Genes (2009)
  • State of the Art Lecture at the ISBT meeting (2000)
  • Keynote Lecture at the Annual Meeting of the Japanese Society of Blood Transfusion (1994)
  • The Jean Julliard Prize from the International Society of Blood Transfusion (1992)

Collaborations

Professor Naruya Saitou, National Institute of Genetics, Mishima, Japan
Professor Antoine Blancher, Faculté de Médecine Purpan, Université Paul Sabatier, (Université de Toulouse III), Toulouse, France
Professor Jaume Bertranpetit, IBE - Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia, Spain

People

Selected publications

Yamamoto F, Cid E, Yamamoto M, Saitou N, Bertranpetit J, Blancher A

An integrative evolution theory of histo-blood group ABO and related genes.

Sci Rep 2014, 4 6601. Epub 13 Oct 2014
The ABO system is one of the most important blood group systems in transfusion/transplantation medicine. However, the evolutionary significance of the ABO gene and its polymorphism remained unknown. We took an integrative approach to gain insights into the significance of the evolutionary process of ABO genes, including those related not only phylogenetically but also functionally. We experimentally created a code table correlating amino acid sequence motifs of the ABO gene-encoded glycosyltransferases with GalNAc (A)/galactose (B) specificity, and assigned A/B specificity to individual ABO genes from various species thus going beyond the simple sequence comparison. Together with genome information and phylogenetic analyses, this assignment revealed early appearance of A and B gene sequences in evolution and potentially non-allelic presence of both gene sequences in some animal species. We argue: Evolution may have suppressed the establishment of two independent, functional A and B genes in most vertebrates and promoted A/B conversion through amino acid substitutions and/or recombination; A/B allelism should have existed in common ancestors of primates; and bacterial ABO genes evolved through horizontal and vertical gene transmission into 2 separate groups encoding glycosyltransferases with distinct sugar specificities.
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Yamamoto M, Cid E, Yamamoto F

Molecular genetic basis of the human Forssman glycolipid antigen negativity.

Sci Rep 2012, 2 975. Epub 13 Dec 2012
Forssman heterophilic glycolipid antigen has structural similarity to the histo-blood group A antigen, and the GBGT1 gene encoding the Forssman glycolipid synthetase (FS) is evolutionarily related to the ABO gene. The antigen is present in various species, but not in others including humans. We have elucidated the molecular genetic basis of the Forssman antigen negativity in humans. In the human GBGT1 gene, we identified two common inactivating missense mutations (c.688G>A [p.Gly230Ser] and c.887A>G [p.Gln296Arg]). The reversion of the two mutations fully restored the glycosyltransferase activity to synthesize the Forssman antigen in vitro. These glycine and glutamine residues are conserved among functional GBGT1 genes in Forssman-positive species. Furthermore, the glycine and serine residues represent those at the corresponding position of the human blood group A and B transferases with GalNAc and galactose specificity, respectively, implicating the crucial role the glycine residue may play in the FS α1,3-GalNAc transferase activity.
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Yamamoto F, Cid E, Yamamoto M, Blancher A

ABO research in the modern era of genomics.

Transfus Med Rev Apr 2012, 26 (2) 103-18. Epub 23 Sep 2011
Research on ABO has advanced significantly in recent years. A database was established to manage the sequence information of an increasing number of novel alleles. Genome sequencings have identified ABO orthologues and paralogues in various organisms and enhanced the knowledge on the evolution of the ABO and related genes. The most prominent advancements include clarification of the association between ABO and different disease processes. For instance, ABO status affects the infectivity of certain strains of Helicobacter pylori and Noroviruses as well as the sequestration and rosetting of red blood cells infected with Plasmodium falciparum. Genome-wide association studies have conclusively linked the ABO locus to pancreatic cancer, venous thromboembolism, and myocardial infarction in the presence of coronary atherosclerosis. These findings suggest ABO's important role in determining an individual's susceptibility to such diseases. Furthermore, our understanding of the structures of A and B transferases and their enzymology has been dramatically improved. ABO has also become a research subject in neurobiology and the preparation of artificial/universal blood and became a topic in the pseudoscience of "blood type diets." With such new progress, it has become evident that ABO is a critical player in the modern era of genomic medicine. This article provides the most up-to-date information regarding ABO genomics.
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Yamamoto F, McNeill PD, Hakomori S

Genomic organization of human histo-blood group ABO genes.

Glycobiology Feb 1995, 5 (1) 51-8.
We have isolated human genomic DNA clones encompassing 30 kbp of the histo-blood group ABO locus. The locations of the exons have been mapped and the nucleotide sequences of the exon-intron boundaries have been determined. The human ABO genes consist of at least seven exons, and the coding sequence in the seven coding exons spans over 18 kb of the genomic DNA. The exons range in size from 28 to 688 bp, with most of the coding sequence lying in exon 7.
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Yamamoto F, Clausen H, White T, Marken J, Hakomori S

Molecular genetic basis of the histo-blood group ABO system.

Nature 17 May 1990, 345 (6272) 229-33.
The histo-blood group ABO, the major human alloantigen system, involves three carbohydrate antigens (ABH). A, B and AB individuals express glycosyltransferase activities converting the H antigen into A or B antigens, whereas O(H) individuals lack such activity. Here we present a molecular basis for the ABO genotypes. The A and B genes differ in a few single-base substitutions, changing four amino-acid residues that may cause differences in A and B transferase specificity. A critical single-base deletion was found in the O gene, which results in an entirely different, inactive protein incapable of modifying the H antigen.
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