Cytokine-regulated expression of survivin in myeloid leukemia
Cytokine-regulated expression of survivin in myeloid leukemia
复制标题
DOI：
10.1182/blood.v97.9.2784
复制
发表时间：
2001-05-01
期刊：
影响因子：
20.3
通讯作者：
Andreeff, M
中科院分区：
文献类型：
--
作者：
Carter, BZ;Milella, M;Andreeff, M
Survivin是凋亡相关基因家族的一员，在所有最常见的癌症中以细胞周期依赖的方式表达，但在正常分化的成人组织中不表达。研究急性髓系白血病（AML）中Survivin的表达及其调控。蛋白质印迹分析检测到生存素在所有髓系白血病细胞系和16 18个原发性AML样本测试。相反，正常的CD 34（+）细胞和正常的外周血单个核细胞不表达或表达非常低水平的生存素。细胞因子刺激增加白血病细胞系和原发性AML样品中生存素的表达。在培养的原代样品中，与对照细胞相比，单一细胞因子刺激显著增加存活素表达，并且G-CSF、GM-CSF和SCF的组合甚至进一步增加存活素水平。相反，全反式维甲酸显着降低生存素蛋白水平在HL-60，OCI-AML 3和NB-4细胞在96小时内，平行于骨髓单核细胞分化的诱导。使用选择性药理学抑制剂，分化参与的丝裂原活化蛋白激酶激酶（MEK）和磷脂酰肌醇-3激酶（PI 3 K）途径被证明在生存素表达的调节。MEK抑制剂PD 98059在静息和GM-CSF刺激的OCI-AML 3细胞中下调生存素表达，而P13 K抑制剂LY 294002仅在GM-CSF刺激下抑制生存素表达。总之，这些结果表明，生存素在髓系白血病中高度表达，并受精氨酸调节，表明造血细胞因子发挥其抗凋亡和促有丝分裂作用，至少部分，通过增加生存素水平。（Blood，2001; 97：2784-2190），2001年，美国血液学会。
Survivin, a member of the inhibitors-of-apoptosis gene family, is expressed in a cell-cycle-dependent manner in all the most common cancers but not in normal differentiated adult tissues. Survivin expression and regulation were examined in acute myeloid leukemia (AML). Survivin was detected by Western blot analysis in all myeloid leukemia cell lines and in 16 of 18 primary AML samples tested. In contrast, normal CD34(+) cells and normal peripheral blood mononuclear cells expressed no or very low levels of survivin, Cytokine stimulation increased survivin expression in leukemic cell lines and in primary AML samples. in cultured primary samples, single-cytokine stimulation substantially increased survivin expression in comparison with control cells, and the combination of G-CSF, GM-CSF, and SCF increased survivin levels even further. Conversely, all-trans retinoic acid significantly decreased survivin protein levels in HL-60, OCI-AML3, and NB-4 cells within 96 hours, parallel to the induction of myelomonocytic differentiation. Using selective pharmacologic inhibitors, the differential involvement of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol-3 kinase (PI3K) pathways were demonstrated in the regulation of survivin expression. The MEK inhibitor PD98059 down-regulated survivin expression in both resting and GM-CSF-stimulated OCI-AML3 cells, whereas the P13K inhibitor LY294002 inhibited survivin expression only on GM-CSF stimulation. In conclusion, these results demonstrate that survivin is highly expressed and cytokine-regulated in myeloid leukemias and suggest that hematopoietic cytokines exert their antiapoptotic and mitogenic effects, at least in part, by increasing survivin levels. (Blood, 2001; 97:2784-2190) 2001 by The American Society of Hematology.