Abstract |
The rare PEL-negative phenotype is one of the last blood groups with an unknown genetic basis. By combining whole-exome sequencing and comparative global proteomic investigations, we found a large deletion in the ABCC4/MRP4 gene encoding an ATP-binding cassette ( ABC) transporter in PEL-negative individuals. The loss of PEL expression on ABCC4-CRISPR-Cas9 K562 cells and its overexpression in ABCC4-transfected cells provided evidence that ABCC4 is the gene underlying the PEL blood group antigen. Although ABCC4 is an important cyclic nucleotide exporter, red blood cells from ABCC4null/PEL-negative individuals exhibited a normal guanosine 3',5'-cyclic monophosphate level, suggesting a compensatory mechanism by other erythroid ABC transporters. Interestingly, PEL-negative individuals showed an impaired platelet aggregation, confirming a role for ABCC4 in platelet function. Finally, we showed that loss-of-function mutations in the ABCC4 gene, associated with leukemia outcome, altered the expression of the PEL antigen. In addition to ABCC4 genotyping, PEL phenotyping could open a new way toward drug dose adjustment for leukemia treatment.
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Authors | Slim Azouzi, Mahmoud Mikdar, Patricia Hermand, Emilie-Fleur Gautier, Virginie Salnot, Alexandra Willemetz, Gaël Nicolas, Cédric Vrignaud, Alexandre Raneri, Patrick Mayeux, Christine Bole-Feysot, Patrick Nitschké, Jean-Pierre Cartron, Yves Colin, Olivier Hermine, Gabriele Jedlitschky, Marc Cloutier, Jessica Constanzo-Yanez, Carole Ethier, Nancy Robitaille, Maryse St-Louis, Caroline Le Van Kim, Thierry Peyrard |
Journal | Blood
(Blood)
Vol. 135
Issue 6
Pg. 441-448
(02 06 2020)
ISSN: 1528-0020 [Electronic] United States |
PMID | 31826245
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2020 by The American Society of Hematology. |
Chemical References |
- ABCC4 protein, human
- Blood Group Antigens
- Multidrug Resistance-Associated Proteins
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Topics |
- Blood Group Antigens
(genetics)
- Blood Platelets
(cytology, metabolism)
- CRISPR-Cas Systems
- Erythroid Cells
(cytology, metabolism)
- Gene Deletion
- Humans
- Multidrug Resistance-Associated Proteins
(genetics)
- Phenotype
- Platelet Aggregation
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