| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
Paroxysmal nocturnal hemoglobinuria (PNH)is an acquired stem cell disorder of a clonal nature that is characterized by various clinical manifestations such as intravascular hemolysis, thrombosis, and marrow failure, and leukemic conversion. Thc entire mechanism of the hemolysis characteristic of PNH has beeen recently clarified. However, the molecular events leading to other clinical manifestations are still unknown. To understand the complex pathophysiology of PNH, the nature of affected PNH clone needs to be uncovered. PNH cells often shows considerable clonal expansion despite its susceptibility to complement and finally occupies patient's bone marrow. Therefore, we expected a growth advantage of PNH clone over normal clones. In fact, hematopoietic progenitor cells obtained from PNH patients showed a preferential hematopoiesis when engrafted in severe combined immunodeficiency mice. To know a growth property of PNH clone, we investigated affected clones in patients with PNH-related
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stem cell disorders such as aplastic anemia (AA) and myelodysplastic syndromes (MDS). Detection frequency of PNH clone was 30% and 10% in patients with AA and MDS, respectively. In type and site of the PIG-A mutations that are responsible for membrane defect of PNH cells were heterogenous, similar to that observed in de novo PNH. There appeared no close correlation between PIG-A mutations and the expansion of PNH clone. Subsequently, we detected two gene fragments that showed predominant expression in PNH cells by mRNA differential display method. One was 700bp cDNA with a sequence like transcription factors, whereas another showed a similar nucleotide sequence to that of spermidine/spermine N1-acetyltransferase, an enzyme operating in polyamine metabolism. Further, we investigated microsatellite instability to explain the conditions favorable for emergence of mutated clones in patients with PNH. However, it appeared to be too uncommon to explain the mutable conditions. To gain insight into the conditions, additional mechanisms other than microsatellite instability need to bc explored. Less
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