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Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia

  • Marisol Betensky
    Affiliations
    Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Daria Babushok
    Affiliations
    Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Jacquelyn J. Roth
    Affiliations
    Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Philip J. Mason
    Affiliations
    Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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  • Author Footnotes
    1 Permanent address: Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California.
    Jaclyn A. Biegel
    Footnotes
    1 Permanent address: Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California.
    Affiliations
    Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Tracy M. Busse
    Affiliations
    Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Yimei Li
    Affiliations
    Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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  • Curt Lind
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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  • Anna Papazoglou
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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  • Dimitri Monos
    Affiliations
    Department of Pathology and Laboratory Medicine, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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  • Gregory Podsakoff
    Affiliations
    Office of Clinical and Translational Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Monica Bessler
    Affiliations
    Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Timothy S. Olson
    Correspondence
    Corresponding author.
    Affiliations
    Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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  • Author Footnotes
    1 Permanent address: Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California.
      Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells. One frequent acquired abnormality is copy-number neutral loss of heterozygosity on chromosome 6p (6p CN-LOH) involving the human leukocyte antigen (HLA) locus. We hypothesized that because 6p CN-LOH clones may arise from selective pressure to escape immune surveillance through deletion of HLA alleles, the development of 6p CN-LOH may affect response to IST. We used single nucleotide polymorphism array genotyping and targeted next-generation sequencing of HLA alleles to assess frequency of 6p CN-LOH, identity of HLA alleles lost through 6p CN-LOH, and impact of 6p CN-LOH on response to IST. 6p CN-LOH clones were present in 11.3% of patients, remained stable over time, and were not associated with development of MDS-defining cytogenetic abnormalities. Notably, no patient with 6p CN-LOH treated with IST achieved a complete response. In summary, clonal 6p CN-LOH in aAA defines a unique subgroup of patients that may provide insights into hematopoietic clonal evolution.

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