Bone Marrow Failure Disorders

An international team from 9 centers, reporting at the 63rd Annual Meeting of the American Society of Hematology (ASH), presented results of a study (abstract 603) testing the hypothesis that in idiopathic aplastic anemia (IAA) and paroxysmal nocturnal hemoglobinuria (PNH), immune evasion occurs in the broad context of "dysfunction of antigen presentation/processing machinery and immune regulatory proteins, beyond HLA molecules, as an effect of immune pressure under T-cell attack." The resulting up-modulation of these pathways, they note, may ultimately promote acquisition of mutations and expansion of immune-resistant clones in patients with IAA and PNH. The investigators performed single-cell RNAseq analysis in early hematopoietic stem and progenitor cells of patients manifesting IAA, observing "dysfunction of antigen presentation machinery, with up-regulation of most of the HLA molecules, proteasome subunits, and endoplasmic reticulum–related organelle transporters." They studied molecular escape mechanisms by genotyping 204 patients with IAA or PNH, using either a targeted platform or whole genome sequencing. The team concluded that their findings indicate that, "following initial immune insult, clonal architecture of residual hematopoiesis can be dominated by multiple modes of immune escape, agonistically participating [in] a mechanism of 'adaptive' clonal recovery, likely in opposition to the 'maladaptive' malignant progression."