Parker Charles J
Division of Hematology and Bone Marrow Transplant, University of Utah School of Medicine and the George E. Whalen Department of Veterans Affairs Medical Center, 500 Foothill Boulevard, Salt Lake City, UT 84114, USA.
Exp Hematol. 2007 Apr;35(4):523-33. doi: 10.1016/j.exphem.2007.01.046.
The molecular basis of PNH is known. Somatic mutation of the X-chromosome gene PIGA accounts for deficiency of glycosyl phosphatidylinositol-anchored proteins (GPI-AP) on affected hematopoietic stem cells and their progeny. However, neither mutant PIGA nor the consequent deficiency of GPI-AP provides a direct explanation for the clonal outgrowth of the mutant stem cells. Therefore, PNH differs from malignant myelopathies in which clonal expansion is directly attributable to a specific, monogenetic event (e.g., t(9;22) in CML) that bestows a growth/survival advantage upon the affected cell. Multiple, discrete PIGA mutant clones are present in many patients, suggesting that a selection pressure that favors the PNH phenotype (i.e., GPI-AP deficiency) was applied to the bone marrow. The nature of this putative selection pressure, however, is speculative, as is the basis of clonal expansion. In many patients, the majority of hematopoiesis is derived from PIGA mutant stem cells. Yet clonal expansion is limited (nonmalignant), and the contribution of the mutant clones to hematopoiesis may remain stable for decades. Understanding the basis of clonal selection and expansion will not only delineate further the pathophysiology of PNH but also provide new insights into stem cell biology and suggest novel therapeutic strategies for enhancing marrow function.
阵发性睡眠性血红蛋白尿症（PNH）的分子基础已为人所知。X染色体基因PIGA的体细胞突变导致受影响的造血干细胞及其子代糖基磷脂酰肌醇锚定蛋白（GPI-AP）缺乏。然而，无论是突变的PIGA还是随之而来的GPI-AP缺乏，都无法直接解释突变干细胞的克隆性增殖。因此，PNH与恶性骨髓疾病不同，在恶性骨髓疾病中，克隆性扩增直接归因于特定的单基因事件（如慢性粒细胞白血病中的t(9;22)），该事件赋予受影响细胞生长/存活优势。许多患者存在多个离散的PIGA突变克隆，这表明骨髓受到了有利于PNH表型（即GPI-AP缺乏）的选择压力。然而，这种假定的选择压力的性质以及克隆性扩增的基础都是推测性的。在许多患者中，大部分造血来源于PIGA突变干细胞。然而，克隆性扩增是有限的（非恶性），并且突变克隆对造血的贡献可能在几十年内保持稳定。了解克隆选择和扩增的基础不仅将进一步阐明PNH的病理生理学，还将为干细胞生物学提供新的见解，并为增强骨髓功能提出新的治疗策略。
