title: Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia.
abstract: Acquired aplastic anemia (aAA) is a nonmalignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20-25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease, even in younger patients. To evaluate clonal hematopoiesis in aAA, we used comparative whole exome sequencing of paired bone marrow and skin samples in 22 patients. We found somatic mutations in 16 patients (72.7%) with a median disease duration of 1 year; of these, 12 (66.7%) were patients with pediatric-onset aAA. Fifty-eight mutations in 51 unique genes were found primarily in pathways of immunity and transcriptional regulation. Most frequently mutated was PIGA, with seven mutations. Only two mutations were in genes recurrently mutated in myelodysplastic syndrome. Two patients had oligoclonal loss of the HLA alleles, linking immune escape to clone emergence. Two patients had activating mutations in key signaling pathways (STAT5B (p.N642H) and CAMK2G (p.T306M)). Our results suggest that clonal hematopoiesis in aAA is common, with two mechanisms emerging-immune escape and increased proliferation. Our findings expand conceptual understanding of this nonneoplastic blood disorder. Future prospective studies of clonal hematopoiesis in aAA will be critical for understanding outcomes and for designing personalized treatment strategies.
authors: Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. Electronic address: daria.babushok@uphs.upenn.edu.
authors: Daria V
authors: DV
authors: Babushok
authors: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Nieves
authors: N
authors: Perdigones
authors: Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Juan C
authors: JC
authors: Perin
authors: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Timothy S
authors: TS
authors: Olson
authors: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Wenda
authors: W
authors: Ye
authors: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Jacquelyn J
authors: JJ
authors: Roth
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Curt
authors: C
authors: Lind
authors: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Carine
authors: C
authors: Cattier
authors: Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Yimei
authors: Y
authors: Li
authors: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Helge
authors: H
authors: Hartung
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Michele E
authors: ME
authors: Paessler
authors: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Dale M
authors: DM
authors: Frank
authors: Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Hongbo M
authors: HM
authors: Xie
authors: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Shanna
authors: S
authors: Cross
authors: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Joshua D
authors: JD
authors: Cockroft
authors: Center for Cellular and Molecular Therapeutics, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Gregory M
authors: GM
authors: Podsakoff
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Dimitrios
authors: D
authors: Monos
authors: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors: Jaclyn A
authors: JA
authors: Biegel
authors: Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Philip J
authors: PJ
authors: Mason
authors: Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Comprehensive Bone Marrow Failure Center, Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors: Monica
authors: M
authors: Bessler
mesh_terms: D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000097:blood / Q000235:genetics*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006410:Hematopoiesis; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D050799:STAT5 Transcription Factor / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; C080086:phosphatidylinositol glycan-class A protein; C517662:CAMK2G protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Clonal hematopoiesis; MDS; aplastic anemia; bone marrow failure; myelodysplastic syndrome