Davis R E, Greenberg P L
Department of Pathology, Stanford University Medical Center and VA Palo Alto Health Care System, CA 94304, USA.
Leuk Res. 1998 Sep;22(9):767-77. doi: 10.1016/s0145-2126(98)00051-4.
the bcl-2 oncogene blocks apoptosis in various cell types and is expressed by normal myeloid precursors, declining with maturation. To investigate whether bcl-2 plays a role in the increase of myeloblasts in myelodysplastic syndromes (MDS) and their progression to acute myeloid leukemia (AML), we studied bcl-2 expression in initial (pre-therapy) bone marrow biopsies from MDS at early (refractory anemia, RA, with or without ring sideroblasts) and advanced stages (RA with excess blasts, and in transformation). Sequential biopsies were also studied to evaluate the effect of time or disease progression, including evolution to AML, or therapy with granulocyte colony stimulating factor (G-CSF). Early myeloid precursors (EMPs), predominantly myeloblasts, were identified in paraffin sections after immunostaining; bcl-2-positive EMPs were enumerated as a percentage of all EMPs (Bcl-2%), and by their absolute frequency per x 900 microscopic field (Bcl-2 index).
in initial biopsies, the Bcl-2% and Bcl-2 index in early MDS (9.9+/-2.6 and 1.4+/-0.6, respectively; mean+/-S.E.) were significantly lower than in advanced MDS (26.4+/-3.6, 4.6+/-1.4), but similar to controls (8.1+/-0.3 and 0.8+/-0.1). The Bcl-2% and Bcl-2 index in three patients with AML evolved from MDS (57.4+/-17.9 and 85.1+/-62.4) were similar to values for seven patients with de novo AML (63.0+/-10.0, 98.4+/-29.8) and significantly higher than values for other groups. Bcl-2% showed relative increments with time or disease progression (range, 21-273%; 11 of 18 sequential biopsies from six of ten MDS patients), which was not clearly altered by G-CSF therapy (four of six patients with, two of four patients without treatment).
bcl-2 expression by EMPs (in both proportion and absolute number) correlated with initial MDS stage, progressed over time independent of G-CSF therapy, and was associated with evolution to AML. These data provide support for the hypothesis that MDS progression is related to accumulation of immature myeloid cells with increased bcl-2 expression and decreased apoptosis.
bcl - 2癌基因可阻止多种细胞类型的凋亡，由正常髓系前体细胞表达，并随细胞成熟而下降。为研究bcl - 2在骨髓增生异常综合征（MDS）中原始粒细胞增多及其向急性髓系白血病（AML）进展过程中是否起作用，我们研究了MDS早期（难治性贫血，RA，伴或不伴环形铁粒幼细胞）和晚期（原始细胞增多的RA及转化期）初诊（治疗前）骨髓活检组织中bcl - 2的表达情况。还对系列活检组织进行研究，以评估时间或疾病进展的影响，包括向AML的演变，或粒细胞集落刺激因子（G - CSF）治疗的影响。免疫染色后在石蜡切片中识别早期髓系前体细胞（EMPs），主要为原始粒细胞；bcl - 2阳性EMPs以其占所有EMPs的百分比（Bcl - 2%）以及每900倍显微镜视野中的绝对频数（Bcl - 2指数）进行计数。
在初诊活检组织中，早期MDS的Bcl - 2%和Bcl - 2指数（分别为9.9±2.6和1.4±0.6；均值±标准误）显著低于晚期MDS（26.4±3.6，4.6±1.4），但与对照组相似（8.1±0.3和0.8±0.1）。3例由MDS演变而来的AML患者的Bcl - 2%和Bcl - 2指数（57.4±17.9和85.1±62.4）与7例原发性AML患者的值相似（63.0±10.0，98.4±29.8），且显著高于其他组。Bcl - 2%随时间或疾病进展呈现相对增加（范围为21 - 273%；10例MDS患者中有6例的18次系列活检中有11次），G - CSF治疗对此无明显改变（6例接受治疗的患者中有4例，4例未治疗的患者中有2例）。
EMPs中bcl - 2的表达（比例和绝对数量）与MDS的初始阶段相关，随时间进展且与G - CSF治疗无关，并与向AML的演变有关。这些数据支持了MDS进展与bcl - 2表达增加和凋亡减少的未成熟髓系细胞积累有关的假说。
