Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation

被引：24

作者：

Azouzi, Slim ^{[1
,2
,3
,4
]}

Mikdar, Mahmoud ^{[1
,2
,3
,4
]}

Hermand, Patricia ^{[1
,2
,4
]}

Gautier, Emilie-Fleur ^{[4
,5
]}

Salnot, Virginie ^{[4
,5
]}

Willemetz, Alexandra ^{[1
,2
,3
,4
]}

Nicolas, Gael ^{[4
,6
]}

Vrignaud, Cedric ^{[1
,2
,3
,4
]}

Raneri, Alexandre ^{[2
,3
]}

Mayeux, Patrick ^{[4
,5
]}

Bole-Feysot, Christine ^{[7
]}

Nitschke, Patrick ^{[8
]}

Cartron, Jean-Pierre ^{[2
]}

Colin, Yves ^{[1
,2
,4
]}

Hermine, Olivier ^{[9
]}

Jedlitschky, Gabriele ^{[10
]}

Cloutier, Marc ^{[11
]}

Constanzo-Yanez, Jessica ^{[12
]}

Ethier, Carole ^{[11
]}

Robitaille, Nancy ^{[12
]}

St-Louis, Maryse ^{[11
]}

Kim, Caroline Le Van ^{[1
,2
,4
]}

Peyrard, Thierry ^{[1
,2
,3
,4
]}

机构：

[1] Univ Paris, Unite Mixte Rech UMR S1134, INSERM, Biol Integree Globule Rouge, Paris, France

[2] Inst Natl Transfus Sanguine, Paris, France

[3] Dept Ctr Natl Reference Grp Sanguins, Paris, France

[4] Lab Excellence GR Ex, Paris, France

[5] Univ Paris, CNRS, Inst Cochin, INSERM,UMR S1016,UMR 8104,Plateforme Prote, Paris, France

[6] Univ Paris, Ctr Rech Inflammat, CNRS, INSERM,UMR S1149,Equipe Rech Label Isee 8252, Paris, France

[7] Univ Paris, Inst Malad Genet IMAGINE, INSERM, Genom Platform,UMR 1163, Paris, France

[8] Univ Paris, IMAGINE, Bioinformat Platform, Paris, France

[9] Univ Paris, CNRS, UMR 8147, Paris, France

[10] Univ Med Greifswald, Ctr Drug Absorpt & Transport, Dept Pharmacol, Greifswald, Germany

[11] Hema Quebec, Quebec City, PQ, Canada

[12] Hema Quebec, Montreal, PQ, Canada

来源：

BLOOD | 2020年 / 135卷 / 06期

关键词：

MAINTENANCE THERAPY; FUNCTIONAL-ANALYSIS; RESISTANCE; PROTEIN; MRP4; POLYMORPHISMS; ABCC4; GENE; CYTOTOXICITY; EXPRESSION;

D O I：

10.1182/blood.2019002320

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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/PELnegative individuals exhibited a normal guanosine 39,59-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.

引用

页码：441 / 448

页数：8

共 43 条

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