Paroxysmal nocturnal haemoglobinuria: a replacement of haematopoietic tissue?
Acquired somatic mutations of the PIG-A gene lead to deficient expression of glycosyl-phosphatidyl-inositol-anchored proteins (GPI-AP) by haematopoietic cells and play a causative role in the pathogenesis of paroxysmal nocturnal haemoglobinuria (PNH). However, PIG-A mutations do not explain how the defective PNH clone can expand. It was hypothesized that a selection process conferring a relative advantage to the GPI-AP-deficient population is required. Since GPI-AP-deficient cells are also detectable in a substantial proportion of patients with otherwise typical aplastic anaemia (AA), the mechanisms inducing bone marrow failure might selectively spare the GPI-deficient cells. In order to examine the growth characteristics of GPI-AP-deficient cells in more detail, we performed repeated analyses of GPI-AP expression on peripheral blood cells in 41 patients with AA. We observed four patterns of the course of GPI-AP-deficient populations: (1) 13 patients showed normal expression of GPI-AP in the first analysis and in at least two follow-up studies at a median time of 709 days after the first analysis. (2) Secondary evolution of a GPI-AP-deficient population was a rare event. Only 4 patients with initially normal GPI-AP expression developed a GPI-AP-deficient population during follow up after immunosuppressive treatment. (3) Persistence of GPI-AP-deficient cells was observed in 16 patients during a median follow-up time of 774 days. However, in some patients, the size of the GPI-AP-deficient population increased substantially. (4) Disappearance of a GPI-AP-deficient population was observed in 8 patients. The time course of GPI-AP expression in relation to the treatment suggests that therapeutic interventions might modulate the ratio of normal versus GPI-AP-deficient haematopoiesis. Overall, these data argue against an 'absolute growth advantage' of GPI-AP-deficient cells. Our data are consistent with the hypothesis that haematopoietic failure caused by damage to normal haematopoiesis allows the outgrowth of a GPI-AP-deficient population. Thus, in at least some patients GPI-AP-deficient cells might pre-exist at a very low percentage and replace haematopoiesis after an insult to the normal cells.
Schrezenmeier
H
H
Free University of Berlin, University Hospital Benjamin Franklin, Medical Clinic III, Berlin, Germany. schrezenmeier@ukbf.fu-berlin.de
Hildebrand
A
A
Rojewski
M
M
Häcker
H
H
Heimpel
H
H
Raghavachar
A
A
D000741:Anemia, Aplastic / Q000473:pathology; D004912:Erythrocytes / Q000737:chemistry / Q000473:pathology; D015870:Gene Expression; D017261:Glycosylphosphatidylinositols / Q000172:deficiency / Q000235:genetics; D006098:Granulocytes / Q000737:chemistry / Q000473:pathology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D007700:Kinetics; D008214:Lymphocytes / Q000737:chemistry / Q000473:pathology; D009000:Monocytes / Q000737:chemistry / Q000473:pathology; D009154:Mutation; D012156:Reticulocytes / Q000737:chemistry / Q000473:pathology
D017261:Glycosylphosphatidylinositols