Clonal dynamics of hematopoietic stem cell compartment in aplastic anemia

Advances in molecular technologies accelerated investigations of the hematopoietic stem cell (HSC) compartment in aplastic anemia (AA). Initially, stem cell biology approaches indicated a profound depletion of HSC pool, while studies of paroxysmal nocturnal hemoglobinuria (PNH), X-chromosome inactivation and cytogenetics provided the first evidence for the presence of clonality in the context of a contracted HSC compartment. More recently, the introduction of deep NGS allowed a more precise assessment of clonal expansions in AA. NGS studies demonstrated that the acquisition of somatic defects, including mutations and copy number alterations, can occur prior to and without a strict consequence of a later evolution of post-AA myelodysplastic syndrome (MDS). Such mutant clones may simply correspond to clonal hematopoiesis of indeterminate potential (CHIP) prematurely uncovered by the depletion of polyclonal "normal" HSCs. However, clonal expansions may also correspond to adaptive responses extrinsically or intrinsically enhancing clonal fitness. These processes could lead to adaptive (clonal non-malignant) or maladaptive (post-AA MDS) attempts at reconstitution of hematopoiesis. The spectrum of molecular events provides many clues as to the evolutionary forces driving the pathogenesis of AA and also valuable lessons as to the function of normal and malignant hematopoiesis. This article summarizes current thinking, controversies and dilemmas in interpreting molecular data obtained from the studies of AA.