Abstract
The typical bone marrow failure syndrome, aplastic anaemia (AA), can be either acquired or inherited. While acquired AA is thought to result from a cytotoxic T-cell mediated immunological attack on hematopoietic stem and progenitor cells, inherited types of AA are caused by the consequences of germline mutations. Clonality in the form of chromosomal abnormalities and single nucleotide variations, hitherto assumed to be a strictly “benign” disease, is now widely acknowledged in AA. Mechanisms behind this clonality probably have to do with the selection of clones that enhance cell survival in immune-attacked marrow or immunological evasion. We now have a better understanding of the genomic environment of aplastic anaemia thanks to the widespread usage and accessibility of next-generation and other genetic sequencing techniques.
Introduction
Experts agree that immune dysregulation resulting in an autoimmune T-cell regulated destruction of hematopoietic and progenitor stem cells is the likely driver. Most patients can be successfully treated with a combination of immunosuppressive therapy (IST) & Eltrombopag (EPAG) or allogeneic bone marrow transplants (BMT). Many AA patients exhibit some form of clonality – be it structural aberrations or somatic gene mutations. Age related clonal hematopoiesis (ARCH) is a common phenomenon observed in the healthy aging population where HSPCs give rise to genetically distinct subpopulation (s) of blood cells. AA patients show an enriched mutational frequency compared to healthy age matched individuals. There are 2 suggested hypotheses for this observation. Clonal evolution to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) may be present. Clonality may also be present due to loss of human leukocyte antigens (HLA) alleles. Somatic mutations in clonal hematopoiesis of indeterminate potential (CHIP) are detected in 30% of AA patients.
Cytogenetic abnormalities in AA
Aplastic anemia originally was thought to be devoid of any clonal abnormalities. However, AA patients have long been known to develop either overt hematologic malignancy or isolated abnormal karyotypes subsequent to IST, and it is now recognized that a subset of patients may present with abnormal cytogenetics, most commonly 13q deletion (del 13q).
Somatic mutations in AA, clonal hematopoiesis of indeterminate significance (CHIP) and myeloid neoplasms
CHIP is defined as the presence of a somatic mutation in a known driver gene at variant allele fraction (VAF) ≥ 2% and serves as a prototypic example of the presence of mutations (often at a low VAF of <10%) without clinically significant cytopenias. The 3 most frequent mutations generally reported are TET2, ASXL1 and DNMT3A. Other reported mutations include PPM1D, JAK2, SF3B1, SRSF2, TP53, GNAS and GNB1.
Therapeutic implications of clonal evolution
AA was once a universally fatal disease, however, advances in BMT, as well as the introduction of horse ATG (hATG) in the 1980s, later with the combination of cyclosporine, as a successful IST regimen has changed the treatment landscape. Current overall response rates to IST range have reached over 70% with the addition of EPAG. However, long term risk of clonal evolution remains a concern in patients who receive IST.
Final conclusions
The immune marrow environment likely shapes the development of clones in AA resulting in immune escape mechanisms or driving malignant transformation. Enhanced mutational profiling, in the era of deep NGS, has improved the diagnostic specificity of identifying myeloid neoplasms and thus clonality is increasingly recognized.
References:
1. T Winkler et al. Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag Blood (2019).
2. BA Patel et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study Blood (2022).
3. A Jerez et al. STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients Blood (2013).
4. MW Wlodarski et al. Molecular strategies for detection and quantitation of clonal cytotoxic T-cell responses in aplastic anemia and myelodysplastic syndrome Blood (2006).
5. JN Kochenderfer et al. Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression (2002).
6. S Pagliuca et al. The similarity of class II HLA genotypes defines patterns of autoreactivity in idiopathic bone marrow failure disorders Blood (2021).
7. Y Zaimoku et al. Identi cation of an HLA class I allele closely involved in the autoantigen presentation in acquired aplastic anemia Blood (2017).
8. M Li et al. Somatic mutations in the transcriptional corepressor gene BCORL1 in adult acute myelogenous leukemia Blood (2011).
9. P Sportoletti et al. BCOR gene alterations in hematologic diseases Blood (2021).
10. F Damm et al. BCOR and BCORL1 mutations in myelodysplastic syndromes and related disorders Blood (2013).
11. JP Maciejewski et al. Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome Blood (2001).
12. S. Ogawa Clonal hematopoiesis in acquired aplastic anemia Blood (2016).
13. P Lundberg et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms Blood (2014).
14. AG Kulasekararaj et al. Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome Blood (2014).
15. L Malcovati et al. Clinical significance of somatic mutation in unexplained blood cytopenia Blood (2017).
16. P Libby et al. Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week. J Am Coll Cardiol (2019).
