Advances in understanding the pathogenesis of acquired aplastic anaemia

Abstract

This review examines the evidence that bone marrow failure (BMF) in aplastic anaemia (AA) is due to loss of haematopoietic stem cells (HSCs), which, in turn, is caused by deranged immunity and inflammation. We also consider how the course of the disease and the response to immuno-suppressive therapy are influenced by the nature and specificity of the pathogenic process. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl-phosphatidyl-inositol -specific auto-immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. A similar process, although less effective, may operate when the auto-immune attack is against a human leucocyte antigen (HLA) molecule and an HLA mutation has produced a clone missing that molecule. We then discuss the significance of other mutant clones that are frequently found in AA, presumably due to a combination of genetic drift and selection. These clones are not causative of AA, but they emerge in AA and they may be pre-leukaemic: unlike a PIGA mutant clone, in general they are unable to effectively reconstitute haematopoiesis.

Diacylglycerol kinase ζ deficiency triggers early signs of aplastic anemia in mice

“…The BM failure in AA is attributed in great measure to the abnormal presence of inflammatory cytokines that promote HSC differentiation, preventing their continuous selfrenewal. 27 HSC activity in the BM is found in a small subset of the lineage marker (Lin) -Sca1 + c-Kit + (LSK) population that gives rise to multipotent progenitors (MMP). 28 Immunophenotype analysis of HSC by flow cytometry showed no differences in the LSK pool in DGKζ -/mice, with a significant decrease in MMP compared to WT mice (Figure 2A).…”

“…In healthy conditions, elevation of inflammatory cytokines such as IFNγ induce rapid differentiation of HSC to the myeloid lineage to respond to infections. Abnormal, chronic IFNγ elevation in AA impairs HSC continuous self-renewal leading to loss of stem precursors 27. The analysis of stem cell populations in DGKζ -/mice reveals an abnormal, high elevation of IFNγ concomitant with a significant decrease in all precursor populations and myeloid mature cells.…”

Acquired Aplastic Anemia as a Clonal Disorder of Hematopoietic Stem Cells

“…This group of mutations has been found to be at risk of inferior prognosis with a higher risk of evolution to MDS and AML [55,89]. DNMT3A mutation is involved in DNA methylation [94,95], ASXL1 belongs to the polycomb family influencing chromatin structure and function [94,96].…”

Advances in Transfusion Medicine RCPath, November 2018

“…Prof. Marsh started her talk by providing the audience with a recap on AA, a serious and life‐threatening disorder due to pancytopenia, with bleeding being the second most common cause of death after infection. The treatment options available are either a haemopoietic stem cell transplant (HSCT) or immunosuppressive therapy (IST), which includes antithymocyte globulin (ATG), and cyclosporine for refractory AA (Quillen et al, ; Hochsmann et al, ; Killick et al, ; Luzzatto & Risitano, ). Exciting developments were touched on as Prof. Marsh talked about the RACE study (Risitano & De Latour, ), a European phase 3 study that aims to evaluate the efficacy of combining standard immunosuppression and Eltrombopag as a first‐line treatment for AA (Townsley et al, ).…”