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.
Keywords
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Article info
Publication history
Published online: February 02, 2015
Accepted:
January 23,
2015
Received in revised form:
January 22,
2015
Received:
January 9,
2015
Identification
Copyright
© 2015 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
