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Blood Adv. 2017 Oct 10;1(22):1900-1910.

Somatic HLA Mutations Expose the Role of Class I-Mediated Autoimmunity in Aplastic Anemia and its Clonal Complications.

Author information

1
Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104.
2
Comprehensive Bone Marrow Failure Center, Department of Pediatrics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104.
3
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104.
4
Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, 3535 Market Street, Philadelphia, PA 19104.
5
Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, 3501 Civic Center Boulevard, Philadelphia, PA 19104.
6
Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
7
Office of Clinical and Translational Research, Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, Philadelphia, PA 19104.
8
Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104.
9
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, 4650 W. Sunset Boulevard, Los Angeles, CA 90033.
10
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104.
11
Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104.

Abstract

Acquired aplastic anemia (aAA) is an acquired deficiency of early hematopoietic cells, characterized by inadequate blood production, and a predisposition to myelodysplastic syndrome (MDS) and leukemia. Although its exact pathogenesis is unknown, aAA is thought to be driven by Human Leukocyte Antigen (HLA)-restricted T cell immunity, with earlier studies favoring HLA class II-mediated pathways. Using whole exome sequencing (WES), we recently identified two aAA patients with somatic mutations in HLA class I genes. We hypothesized that HLA class I mutations are pathognomonic for autoimmunity in aAA, but were previously underappreciated because the Major Histocompatibility Complex (MHC) region is notoriously difficult to analyze by WES. Using a combination of targeted deep sequencing of HLA class I genes and single nucleotide polymorphism array (SNP-A) genotyping we screened 66 aAA patients for somatic HLA class I loss. We found somatic HLA loss in eleven patients (17%), with thirteen loss-of-function mutations in HLA-A*33:03, HLA-A*68:01, HLA-B*14:02 and HLA-B*40:02 alleles. Three patients had more than one mutation targeting the same HLA allele. Interestingly, HLA-B*14:02 and HLA-B*40:02 were significantly overrepresented in aAA patients, compared to ethnicity-matched controls. Patients who inherited the targeted HLA alleles, regardless of HLA mutation status, had a more severe disease course with more frequent clonal complications as assessed by WES, SNP-A, and metaphase cytogenetics, and more frequent secondary MDS. The finding of recurrent HLA class I mutations provides compelling evidence for a predominant HLA class I-driven autoimmunity in aAA, and establishes a novel link between aAA patients' immunogenetics and clonal evolution.

KEYWORDS:

HLA; aplastic anemia; autoimmunity; clonal hematopoiesis; myelodysplastic syndrome

PMID:
28971166
PMCID:
PMC5621748

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