Abstract 2977: Most patients with acquired aplastic anemia develop clonal hematopoiesis early in disease
Authors: Babushok Daria V. , Perdigones Nieves , Perin Juan C. , Olson Timothy S. , Ye Wenda , Roth Jacquelyn J. , Lind Curt , Cattier Carine , Li Yimei , Hartung Helge , Paessler Michele E. , Frank Dale M. , Xie Hongbo M. , Busse Tracy M. , Cross Shanna , Podsakoff Gregory M. , Monos Dimitrios , Biegel Jaclyn A. , Mason Philip J. , Bessler Monica 
Published: August 2015

Clonal hematopoiesis is an expansion of hematopoietic stem cells, caused by somatic mutations or epigenetic changes that confer a growth advantage to the host cell. Although recently recognized as a phenomenon of aging, clonal hematopoiesis has been traditionally associated with pre-cancerous states and malignant transformation. Acquired aplastic anemia (AA), a non-neoplastic autoimmune blood disorder occurring in children and adults, has been associated with clonal hematopoietic disorders; transformation to myelodysplastic syndrome (MDS) or acute leukemia is a late complication in 10-15% of AA patients. Based on the association of AA with clonal disorders, we hypothesized that clonal hematopoiesis is a general phenomenon in AA, and can be seen in the majority of AA patients, including children. To evaluate somatic genetic changes in AA, we used a combination of single nucleotide polymorphism array (SNP-A) genotyping and comparative whole exome sequencing of paired bone marrow aspirates and skin in twenty nine patients with AA. All somatic mutations were validated by bi-directional Sanger sequencing. The median age of diagnosis was 14 years (range 1.5-65). Patients were analyzed at a median of 1.1 years from diagnosis. None of the patients had histopathological evidence of MDS at the time of analysis. Somatic mutations were identified in the majority of patients, including patients with pediatric-onset AA. Three patients (10%) had somatic loss-of-function mutations in HLA class I alleles. Although MDS-associated mutations were identified in 2 of 29 patients, the majority of mutations were not in genes associated with MDS and hematologic malignancies. Pathway analysis of mutated genes revealed an enrichment of genes in pathways of immunity and transcriptional regulation. Comparison of somatic mutations in AA to a patient with a 30-year history of AA who progressed to MDS revealed that, unlike in AA, which was characterized by diverse and frequently oligoclonal hematopoiesis, progression to MDS was associated with an expansion of a dominant clone carrying multiple classical mutations linked to malignancy: pathogenic mutations in SUZ12 (homozygous for the mutated region due to copy number-neutral loss of heterozygosity (CN-LOH) at the chromosomal region 17q11.2qter), ASXL1, RUNX1, and PHF6. In conclusion, our data show that clonal hematopoiesis emerges in the majority of patients with AA, including children and young adults, can be detected early in disease, and has a mutational spectrum largely distinct from MDS. Our results highlight that in the absence of morphologic features of myelodysplasia, the presence of clonal hematopoiesis with somatic mutations cannot be used to distinguish MDS from AA. Future longitudinal studies of clonal hematopoiesis in AA will help to explain differences in patients’ disease course, and will enable personalized treatment approaches in AA.

Citation Format: Daria V. Babushok, Nieves Perdigones, Juan C. Perin, Timothy S. Olson, Wenda Ye, Jacquelyn J. Roth, Curt Lind, Carine Cattier, Yimei Li, Helge Hartung, Michele E. Paessler, Dale M. Frank, Hongbo M. Xie, Tracy M. Busse, Shanna Cross, Gregory M. Podsakoff, Dimitrios Monos, Jaclyn A. Biegel, Philip J. Mason, Monica Bessler. Most patients with acquired aplastic anemia develop clonal hematopoiesis early in disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2977. doi:10.1158/1538-7445.AM2015-2977