Coustan-Smith E, Kitanaka A, Pui C H, McNinch L, Evans W E, Raimondi S C, Behm F G, Aricò M, Campana D
Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis TN 38101, USA.
Blood. 1996 Feb 1;87(3):1140-6.
Enforced BCL-2 gene expression in leukemic cell lines suppresses apoptosis and confers resistance to anticancer drugs, but the clinical significance of increased BCL-2 protein levels in acute lymphoblastic leukemia (ALL) is unknown. Among 52 children with newly diagnosed ALL, BCL-2 expression in leukemic lymphoblasts ranged widely, from 4,464 to 59,753 molecules of equivalent soluble fluorochrome per cell (MESF), as determined by flow cytometry. The mean (+/- SD) level of MESF in 43 cases of B-lineage ALL (19,410 +/- 11,834) was higher than that detected in CD10+ B-lymphoid progenitors from normal bone marrow (450 +/- 314; P < .001), and CD19+ peripheral blood B lymphocytes (7,617 +/- 1,731; P = .02). Levels of BCL-2 in T-ALL cases (17,909 +/- 18,691) were also generally higher than those found in normal CD1a+ thymocytes (1,762 +/- 670), or in peripheral blood T lymphocytes (9,687 +/- 3,019). Although higher levels of BCL-2 corresponded to higher leukemic cell recoveries after culture in serum-free medium, they did not correlate with higher cell recoveries after culture on stromal layers, or with in vitro resistance to vincristine, dexamethasone, 6-thioguanine, cytarabine, teniposide, daunorubicin or methotrexate. BCL-2 protein levels did not correlate with presenting clinical features. Unexpectedly, however, lower-than-median MESF values were significantly associated with the presence of chromosomal translocations (P = .010). Notably, all six cases with the Philadelphia chromosome, a known high-risk feature, had low levels of BCL-2 expression (P = .022). Higher levels of BCL-2 were not associated with poorer responses to therapy among 33 uniformly treated patients, and were not observed in three patients studied at relapse. In conclusion, increased BCL-2 expression in childhood ALL appears to enhance the ability of lymphoblasts to survive without essential trophic factors, and is inversely related to the presence of chromosomal translocations. However, it does not reflect increased disease aggressiveness or resistance to chemotherapy.
白血病细胞系中强制表达BCL-2基因可抑制细胞凋亡并赋予抗癌药物耐药性，但急性淋巴细胞白血病（ALL）中BCL-2蛋白水平升高的临床意义尚不清楚。在52例新诊断的ALL儿童中，通过流式细胞术测定，白血病原始淋巴细胞中的BCL-2表达范围广泛，每细胞等效可溶性荧光染料分子数（MESF）从4464到59753不等。43例B系ALL（19410±11834）的MESF平均（±标准差）水平高于正常骨髓中CD10+B淋巴细胞祖细胞（450±314；P<.001）和CD19+外周血B淋巴细胞（7617±1731；P=.02）中的检测水平。T-ALL病例（17909±18691）中的BCL-2水平通常也高于正常CD1a+胸腺细胞（1762±670）或外周血T淋巴细胞（9687±3019）中的水平。虽然较高的BCL-2水平与无血清培养基培养后较高的白血病细胞回收率相对应，但它们与基质层培养后的较高细胞回收率或与长春新碱、地塞米松、6-硫鸟嘌呤、阿糖胞苷、替尼泊苷、柔红霉素或甲氨蝶呤的体外耐药性无关。BCL-2蛋白水平与呈现的临床特征无关。然而，出乎意料的是，低于中位数的MESF值与染色体易位的存在显著相关（P=.010）。值得注意 的是，所有6例具有费城染色体（一种已知的高危特征）的病例，BCL-2表达水平都很低（P=.022）。在33例接受统一治疗的患者中，较高的BCL-2水平与较差的治疗反应无关，并且在3例复发患者中未观察到。总之，儿童ALL中BCL-2表达增加似乎增强了原始淋巴细胞在没有必需营养因子的情况下存活的能力，并且与染色体易位的存在呈负相关。然而，它并不反映疾病侵袭性增加或对化疗的耐药性。
