Gupta P, Niehans G A, LeRoy S C, Gupta K, Morrison V A, Schultz C, Knapp D J, Kratzke R A
Department of Medicine, Veterans Administration Medical Center and University of Minnesota Medical School, Minneapolis 55417, USA.
Leukemia. 1999 Jan;13(1):44-53. doi: 10.1038/sj.leu.2401233.
Increased apoptosis in the bone marrow (BM) may contribute to the cytopenias that occur in myelodysplastic syndromes (MDS). The Fas receptor, Fas ligand (FasL) pathway is a major mechanism of apoptosis. Since hematopoietic progenitors can express the Fas receptor, they may be susceptible to apoptosis induced by FasL-expressing cells. We examined FasL expression in the BM of patients with MDS (n = 50), de novo acute myeloid leukemia (AML; n = 10), AML following prior MDS (n = 6), and normal controls (n = 6). Compared to controls, FasL expression was increased in MDS, and was highest in AML. In MDS, FasL expression was seen in myeloid blasts, erythroblasts, maturing myeloid cells, megakaryocytes and dysplastic cells, whereas in AML, intense expression was seen in the blasts. FasL expression correlated with the FAB subtype groups of MDS, and also correlated directly with the percentage of abnormal metaphases on cytogenetic analysis. The FasL expressed in MDS BM inhibited the growth of clonogenic hematopoietic progenitors. This inhibition could be blocked by a soluble recombinant FasFc protein. In MDS, FasL expression in the initial diagnostic BM was higher in patients who were more anemic, correlated directly with red cell transfusion requirements over the subsequent course of the disease, and was predictive of survival. These studies indicate that FasL expression in MDS is of prognostic significance, and suggest that pharmacological blockade of the Fas-FasL pathway may be of clinical benefit.
骨髓（BM）中凋亡增加可能导致骨髓增生异常综合征（MDS）中出现的血细胞减少。Fas受体、Fas配体（FasL）途径是凋亡的主要机制。由于造血祖细胞可表达Fas受体，它们可能易受表达FasL的细胞诱导的凋亡影响。我们检测了MDS患者（n = 50）、初发急性髓系白血病（AML；n = 10）、先前MDS后发生的AML（n = 6）以及正常对照（n = 6）的骨髓中FasL的表达。与对照组相比，MDS中FasL表达增加，且在AML中最高。在MDS中，FasL表达见于髓系原始细胞、幼红细胞、成熟髓系细胞、巨核细胞和发育异常细胞，而在AML中，原始细胞中可见强烈表达。FasL表达与MDS的FAB亚型组相关，也与细胞遗传学分析中异常中期的百分比直接相关。MDS骨髓中表达的FasL抑制克隆性造血祖细胞的生长。这种抑制可被可溶性重组FasFc蛋白阻断。在MDS中，初诊骨髓中FasL表达在贫血更严重的患者中更高，与疾病后续过程中的红细胞输血需求直接相关，并可预测生存。这些研究表明MDS中FasL表达具有预后意义，并提示Fas - FasL途径的药理学阻断可能具有临床益处。
