The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS
The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS
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DOI：
10.1182/blood.v96.12.3932.h8003932_3932_3938
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发表时间：
2000-12-01
期刊：
影响因子：
20.3
通讯作者：
Pagliuca, A
中科院分区：
文献类型：
--
作者：
Parker, JE;Mufti, GJ;Pagliuca, A
采用流式细胞术检测102例骨髓增生异常综合征（MDS）和继发于MDS的急性髓系白血病（MDS-AML）患者及30例正常人（NBM）骨髓CD 34（+）细胞凋亡（Annexin V）、增殖（Ki-67）和Bcl-2相关蛋白表达。与NBM（16.7% [3.4%-35.3%]，P <0.0001）相比，难治性贫血（RA）/RA伴环形铁粒幼细胞（RARS）（56.9% [20.4%-93.6%]）和难治性贫血伴原始细胞过多（RAEB）（51.2% [25.2%-76.6%]）中细胞凋亡显著增加。在RA/RARS中，凋亡始终超过增殖（Ki-67阳性，26.1% [9.5%-47.8%];凋亡：增殖比2.08 [1.15-3.63]）;而在RAEB中，由于增殖增加（40.4% [22%-69.5%]），该比值相等（1.14 [0.93-2.08]）。进展为RAEB转化（RAEB-t）/MDS-AML与细胞凋亡显著减少相关。（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]），促凋亡（Bax/Bad）与抗凋亡（Bcl-2/Bcl-X）Bcl-2相关蛋白比值在RA/RARS中较NBM中升高（2.57 [1.93-9.42] vs 1.89 [0.65-4.1]; P = 0.06），而疾病进展与显著降低的比率相关（1.16 [0.06-3.32]; P < .0001）主要由于Bcl-2表达增加。细胞凋亡和Bax/Bad：Bcl-2/Bcl-X比率与国际预后评分系统评分和细胞遗传学风险组呈负相关;在评分低和/或细胞遗传学风险良好的患者中观察到最高水平。Bcl-2相关蛋白表达与细胞凋亡之间存在相关性（P = 0.07）。这项研究表明，MDS的进展是通过多次打击，改变CD 34（+）细胞凋亡和增殖的水平。早期疾病与过度凋亡和凋亡与增殖比率升高有关。在RAEB中观察到增殖率增加，而白血病转化是通过抑制细胞凋亡而不是过度细胞生长而产生的。尽管疾病进展伴随着促凋亡与抗凋亡Bcl-2相关蛋白比率的下降，但蛋白表达模式的异质性表明，除了Bcl-2家族成员之外的其他因素在MDS中的凋亡失调中发挥作用。(C)2000年，美国血液学会。
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. (C) 2000 by The American Society of Hematology.