Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal blood disorder characterized by hemolysis and a high risk of thrombosis, that is due to a deficiency in several cell surface proteins that prevent complement activation. Its origin has been traced to a somatic mutation in the PIG-A gene within hematopoietic stem cells (HSC). However, to date the question of how this mutant clone expands in size to contribute significantly to hematopoiesis remains under debate. One hypothesis posits the existence of a selective advantage of PIG-A mutated cells due to an immune mediated attack on normal HSC, but the evidence supporting this hypothesis is inconclusive. An alternative (and simpler) explanation attributes clonal expansion to neutral drift, in which case selection neither favours nor inhibits expansion of PIG-A mutated HSC. Here we examine the implications of the neutral drift model by numerically evolving a Markov chain for the probabilities of all possible outcomes, and investigate the possible occurrence and evolution, within this framework, of multiple independently arising clones within the HSC pool. Predictions of the model agree well with the known incidence of the disease and average age at diagnosis. Notwithstanding the slight difference in clonal expansion rates between our results and those reported in the literature, our model results lead to a relative stability of clone size when averaging multiple cases, in accord with what has been observed in human trials. The probability of a patient harbouring a second clone in the HSC pool was found to be extremely low (). Thus our results suggest that in clinical cases of PNH where two independent clones of mutant cells are observed, only one of those is likely to have originated in the HSC pool.
Highlights
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder of hematopoietic stem cells (HSC) due to a somatic mutation in the PIG-A gene [1, 2]
The mechanisms leading to expansion of HSC with mutations in the PIG-A gene that leads to the PNH phenotype remains unclear
We propose that PNH is perhaps the first disease where neutral drift alone may be responsible for clonal expansion leading to a clinical problem
Summary
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder of hematopoietic stem cells (HSC) due to a somatic mutation in the PIG-A gene [1, 2]. Many cell surface proteins that need this anchor to attach to the plasma membrane are no longer available or only available in reduced numbers on the cell [3, 4]. Some of these proteins such as CD55 and CD59 are essential for the protection of red blood cells from complement mediated lysis. Scavenging of nitric oxide by free plasma hemoglobin results in endothelial and platelet dysfunction leading to the high risk of venous and arterial thrombosis associated with this disease. Additional symptoms related to nitric oxide depletion include abdominal pain, esophageal pain, chronic kidney disease and erectile dysfunction
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