Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia.
Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia.
复制标题
DOI：
10.1182/blood.v95.7.2364
复制
发表时间：
2000-04
期刊：
影响因子：
20.3
通讯作者：
W. Stock;T. Tsai;C. Golden;C. Rankin;Dorrie Sher;M. Slovak;M. Pallavicini;J. Radich;D. Boldt
中科院分区：
文献类型：
--
作者：
W. Stock;T. Tsai;C. Golden;C. Rankin;Dorrie Sher;M. Slovak;M. Pallavicini;J. Radich;D. Boldt
为了验证细胞周期调节基因异常是成人急性淋巴细胞白血病（ALL）临床结果的决定因素这一假设，我们筛选了西南肿瘤小组方案中视网膜母细胞瘤（Rb）、p53、p15（INK4B）和p16（INK4A）基因异常的患者的淋巴母细胞。33例（85%）患者出现异常表达，频率如下：Rb， 51%；p16 (INK4A) 41%;p53, 26%。13例患者（33%）有2个或2个以上基因异常。比较0到1个异常患者和多个异常患者的结果。两组在大量临床和实验室特征上没有差异。0 - 1和多重异常患者的CR率相似（分别为69%和54%）。0到1个异常患者的中位生存时间为25个月（n = 26; 95% CI， 13-46个月），而多发性异常患者的中位生存时间为8个月（n = 13; 95% CI， 4-12个月）（P < 0.01）。从成人ALL骨髓中分离干细胞（CD34+lin-），免疫细胞化学检测p16（INK4A）的表达。5例患者中有3例淋巴母细胞和分选干细胞缺乏p16（INK4A）表达。在另外2例患者中，只有50%的分选干细胞表达p16（INK4A）。相比之下，在9例淋巴细胞表达p16（INK4A）的患者中，95%（中位数）在CD34+ lin-腔室中表达p16。因此，细胞周期调控基因异常经常出现在成人ALL淋巴细胞中，它们可能是疾病结局的重要决定因素。在干室中出现这些异常表明它们有助于白血病的发生。根除含有这些异常的干细胞亚群可能对实现治愈很重要。
To test the hypothesis that cell cycle regulatory gene abnormalities are determinants of clinical outcome in adult acute lymphoblastic leukemia (ALL), we screened lymphoblasts from patients on a Southwest Oncology Group protocol for abnormalities of the genes, retinoblastoma (Rb), p53, p15(INK4B), and p16(INK4A). Aberrant expression occurred in 33 (85%) patients in the following frequencies: Rb, 51%; p16(INK4A), 41%; p53, 26%. Thirteen patients (33%) had abnormalities in 2 or more genes. Outcomes were compared in patients with 0 to 1 abnormality versus patients with multiple abnormalities. The 2 groups did not differ in a large number of clinical and laboratory characteristics. The CR rates for patients with 0 to 1 and multiple abnormalities were similar (69% and 54%, respectively). Patients with 0 to 1 abnormality had a median survival time of 25 months (n = 26; 95% CI, 13-46 months) versus 8 months (n = 13; 95% CI, 4-12 months) for those with multiple abnormalities (P <.01). Stem cells (CD34+lin-) were isolated from adult ALL bone marrows and tested for p16(INK4A) expression by immunocytochemistry. In 3 of 5 patients lymphoblasts and sorted stem cells lacked p16(INK4A) expression. In 2 other patients only 50% of sorted stem cells expressed p16(INK4A). By contrast, p16 expression was present in the CD34+ lin- compartment in 95% (median) of 9 patients whose lymphoblasts expressed p16(INK4A). Therefore, cell cycle regulatory gene abnormalities are frequently present in adult ALL lymphoblasts, and they may be important determinants of disease outcome. The presence of these abnormalities in the stem compartment suggests that they contribute to leukemogenesis. Eradication of the stem cell subset harboring these abnormalities may be important to achieve cure.