Parker J E, Mufti G J, Rasool F, Mijovic A, Devereux S, Pagliuca A
Department of Haematological Medicine, Guy's, King's, Thomas' School of Medicine, London, United Kingdom.
Blood. 2000 Dec 1;96(12):3932-8.
Bone marrow CD34(+) cell apoptosis (annexin V), proliferation (Ki-67), and Bcl-2-related protein expression was evaluated by flow cytometry in 102 patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia secondary to MDS (MDS-AML) and in 30 normal donors (NBM). Apoptosis was significantly increased in refractory anemia (RA)/RA with ringed sideroblasts (RARS) (56.9% [20.4%-93.6%]) and refractory anemia with excess blasts (RAEB) (51.2% [25.2%-76. 6%]) compared with NBM (16.7% [3.4%-35.3%], P <.0001). In RA/RARS, apoptosis always exceeded proliferation (Ki-67-positivity, 26.1% [9.5%-47.8%]; apoptosis:proliferation ratio 2.08 [1.15-3.63]); whereas in RAEB, this ratio equalized (1.14 [0.93-2.08]) due to increased proliferation (40.4% [22%-69.5%]). Progression to RAEB in transformation (RAEB-t)/MDS-AML was associated with a significant reduction in apoptosis (22.3% [2.1%-53.2%]; P <.0001) and proliferation (16.8% [1.9%-75.8%); P =.04; ratio 1.69 [0.16-12.21]). Pro-apoptotic (Bax/Bad) versus anti-apoptotic (Bcl-2/Bcl-X) Bcl-2-related protein ratios were increased in RA/RARS compared with NBM (2.57 [1.93-9.42] versus 1.89 [0.65-4.1]; P =.06), whereas disease progression was associated with significantly reduced ratios (1.16 [0.06-3.32]; P <.0001) due primarily to increased Bcl-2 expression. Apoptosis and Bax/Bad:Bcl-2/Bcl-X ratio were inversely correlated with both International Prognostic Scoring System score and cytogenetic risk group; highest levels observed in patients with low score and/or good risk cytogenetics. There was a trend toward an association between Bcl-2-related protein expression and apoptosis (P =.07). This study indicates that MDS progression arises through multiple hits that alter levels of CD34(+) cell apoptosis and proliferation. Early disease is associated with excessive apoptosis and elevated ratio of apoptosis to proliferation. Increased proliferative rates are observed in RAEB, whereas leukemic transformation arises through inhibition of apoptosis rather than excessive cell growth. Although disease progression is accompanied by a fall in pro-apoptotic versus anti-apoptotic Bcl-2-related protein ratios, heterogeneity in patterns of protein expression indicates that factors additional to Bcl-2 family members play a role in the deregulated apoptosis in MDS. (Blood. 2000;96:3932-3938)
采用流式细胞术对102例骨髓增生异常综合征（MDS）及继发于MDS的急性髓系白血病（MDS-AML）患者和30例正常供者（正常骨髓，NBM）的骨髓CD34(+)细胞凋亡（膜联蛋白V）、增殖（Ki-67）及Bcl-2相关蛋白表达进行评估。与NBM（16.7% [3.4%-35.3%]，P<.0001）相比，难治性贫血（RA）/伴有环形铁粒幼细胞的RA（RARS）（56.9% [20.4%-93.6%]）及伴有过多原始细胞的难治性贫血（RAEB）（51.2% [25.2%-76.6%]）患者的凋亡显著增加。在RA/RARS中，凋亡总是超过增殖（Ki-67阳性率，26.1% [9.5%-47.8%]；凋亡:增殖比值2.08 [1.15-3.63]）；而在RAEB中，由于增殖增加（40.4% [22%-69.5%]），该比值达到平衡（1.14 [0.93-2.08]）。转化中的RAEB（RAEB-t）/MDS-AML患者的凋亡（22.3% [2.1%-53.2%]；P<.0001）和增殖（16.8% [1.9%-75.8%]；P=.04；比值1.69 [0.16-12.21]）显著降低。与NBM相比，RA/RARS中促凋亡（Bax/Bad）与抗凋亡（Bcl-2/Bcl-X）Bcl-2相关蛋白比值升高（2.57 [1.93-9.42] 对1.89 [0.65-4.1]；P=.06），而疾病进展与比值显著降低相关（1.16 [0.06-3.32]；P<.0001），主要是由于Bcl-2表达增加。凋亡及Bax/Bad:Bcl-2/Bcl-X比值与国际预后评分系统评分及细胞遗传学风险组均呈负相关；在低评分和/或细胞遗传学风险良好的患者中观察到最高水平。Bcl-2相关蛋白表达与凋亡之间存在关联趋势（P=.07）。本研究表明，MDS进展是通过多个影响因素改变CD34(+)细胞凋亡和增殖水平而发生的。早期疾病与过度凋亡及凋亡与增殖比值升高有关。在RAEB中观察到增殖率增加，而白血病转化是通过抑制凋亡而非细胞过度生长发生的。尽管疾病进展伴随着促凋亡与抗凋亡Bcl-2相关蛋白比值下降，但蛋白表达模式的异质性表明，除Bcl-2家族成员外，其他因素也在MDS失调的凋亡中起作用。（《血液》.2000；96:3932-3938）
