Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia.
Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia.
复制标题
DOI：
10.1172/jci12807
复制
发表时间：
2001-09-01
影响因子：
15.9
通讯作者：
Andreeff, M
中科院分区：
文献类型：
--
作者：
Milella, M;Kornblau, SM;Andreeff, M
丝裂原活化蛋白激酶(MAPK)通路调节多种细胞类型的生长和存活，其结构性激活与多种恶性肿瘤的发病机制有关。在这项研究中，我们证明了小分子MEK抑制剂(PD98059和PD184352)对具有结构性MAPK激活的急性髓系白血病(AML)细胞系和原代样本的细胞生长和生存造成严重损害。这些药物消除了白血病细胞的克隆性，但对正常造血祖细胞的影响很小。MEK阻滞剂还可导致对自发和药物诱导的细胞凋亡的敏化。在分子水平上，这些作用与细胞周期蛋白依赖蛋白抑制物(p27(Kip1)和p21(Waf1/CIP1))以及抗凋亡蛋白(IAP)和Bcl2家族的抗凋亡蛋白表达的调节有关。因此，阻断组成性MEK/MAPK信号通路是治疗急性髓系白血病的一种很有前途的策略。
The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and anti-apoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.