Work

Is nature truly healing itself? Spontaneous remissions in Paroxysmal Nocturnal Hemoglobinuria

Year: 2021

Type: article

Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is considered to be curable only through the means of allogeneic stem cell transplantation (SCT) [ 1 ]. One of the many fascinating and scientifically instructive aspects of the pathogenesis of this disease is the unique possibility of its spontaneous remission with disappearance of PNH cell populations and abatement of clinical symptoms, a rare event which has always captivated the research community [ 2 , 3 , 4 ]. Due to the orphan nature of the condition, no clinical predictors have been identified so far as harbingers of this phenomenon estimated to occur in up to 15% (3–15% according to the different series) of PNH patients between 10 and 20 years from disease onset [ 3 , 5 ]. In a classical scenario, exhaustion of the PNH clone (theory of “finite life span”) may be associated with reappearance of aplastic anemia (AA), in which the emergence of a PNH clone reflects a semi-maladaptive attempt of recovery [ 3 ]. Consequently, one could stipulate that a retraction of the PNH clone would have to be associated with a compensatory re-establishment of normal hematopoiesis should normal blood counts be maintained [ 6 ]. The latter hypothesis is supported by anecdotal cases of PNH following autologous SCT (ASCT), in which PNH expansion would be favored by either post-ASCT stem cell pool contraction or immune system derangements, with subsequent extinction of the PNH cell populations upon cessation of these supporting conditions [ 6 , 7 ]. Environmental changes underlying PNH clone expansion/contraction may also provide support for the theory of the “neutral drift” which, by applying in silico models of Markovian stochastic dynamics, posits the absence of a selective advantage of PIGA mutant clones [ 8 , 9 ]. Furthermore, the recent insights into the AA/PNH pathobiology shed light onto molecular underpinnings of polyclonal vs. oligoclonal hematopoiesis and their dynamics as to the possible acquisition over time of clonal hematopoiesis of indeterminate potential (CHIP) [ 10 , 11 ]. Nevertheless, literature data on genetics of PNH spontaneous remission are scarce with to date only one case molecularly characterized by means of modern technologies (e.g., whole-exome sequencing) [ 2 ]. Herein, through the application of multiple next-generation sequencing (NGS) panels interrogating genes involved in PNH clonal evolution, we attempted to better discern the genomic mechanisms of its spontaneous remission.

Source: Blood Cancer Journal

DOI: 10.1038/s41408-021-00582-5