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

Abstract

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.

Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia

“…On the other hand, a recent analysis of 256 severe AA patients, including 33 6pLOH(+) patients, who were treated with horse ATG in the United States failed to show a better response rate in comparison to 6pLOH(-) patients [10]. Another recent study by Betensky et al detected 6pLOH in eight (11.3%) of 71 patients with bone marrow failure using a SNP array analysis and found no significant difference in the response rate to IST between 6pLOH(+) patients and 6pLOH(-) patients (50% v. 77.8%) [24]. The lower response rate to IST in the two studies from the USA than ours may be attributed to the lower sensitivity of the SNP array analysis in comparison to FCM in the detection 6pLOH(+) leukocytes, which could underestimate the prevalence of 6pLOH(+) patients.…”

Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack

“…6 The copy-number neutral loss of heterozygosity in the short arm of chromosome 6 (6pLOH) caused by acquired uniparental disomy is a common abnormality documented in AA patients with clonal hematopoiesis. [7][8][9][10][11][12] Although 6pLOH 1 HSCs are thought to escape the CTL attack and induce clonal hematopoiesis by HLA class I-lacking (HLA 2 ) leukocytes, the precise mechanisms underlying such clonal hematopoiesis remain unknown.…”

False homozygous HLA genotyping results due to copy number neutral loss of heterozygosity in acquired aplastic anaemia

“…Two papers were published describing the frequency and clinical impact of copy number neutral loss of heterozygocity (CN-LOH) of chromosome 6p. Frequency was 13% in a Japanese cohort4 and 11.3% in a Caucasian cohort 5. In aAA, CN-LOH clones tend to be stable in time without the development of MDS-associated cytogenetic abnormalities5 in the Caucasian cohort.…”

“…Hypothesis was made of the same escape mechanism from autoreactive CTLs in aAA 9. It is described in aAA even without previous therapy 5. In severe aplastic anaemia, a treatment algorithm can be followed in which the availability of a matched sibling donor plays a central role 10…”