Mazzacurati Lucia, Pattacini Laura, Brusa Gianluca, Mancini Manuela, Benvenuti Michela, Barbieri Enza, Martinelli Giovanni, Baccarani Michele, Greenberger Joel S, Santucci Maria Alessandra
Istituto di Ematologia e Oncologia Medica Lorenzo e Ariosto Seràgnoli, University of Bologna, Medical School, Bologna, Italy.
Hematol J. 2004;5(2):168-77. doi: 10.1038/sj.thj.6200365.
STI571 is the most innovative drug for the cure of Chronic Myeloid Leukemia. It inhibits, in fact, the disease causative event, the p210 bcr-abl tyrosine kinase, and addresses clonal myeloid progenitors to apoptotic death. Here, we demonstrated that STI571 also induces growth arrest by activating the Chk2-Cdc25A-Cdk2 axis, a pathway complementary to p53 in the activation of G(1)/S cell cycle checkpoint. In vitro exposure to STI571 of 32D murine myeloid progenitor cell clones transducing a temperature-sensitive p210 bcr-abl construct was associated with Chk2 phosphorylation and activation, Cdc25A degradation and persistent Cdk2 inhibitory phosphorylation, preventing, in turn, cell transition to and progression throughout the S phase of cell cycle. Chk2 and Cdc25A are both components of a complex network that integrates signals involved in regulated cell cycle progression, DNA repair and cell decision between life or death. Chk2 gene mutations or decreased expression, leading to its protein loss of function on Cdc25A target, and Cdc25A overexpression have been linked to poor prognosis of human cancers. In CML, they might further enhance the proliferative advantage and genomic instability of clonal myeloid progenitors featuring a class of poor prognosis patients eventually resistant to STI571.
STI571是治疗慢性粒细胞白血病最具创新性的药物。事实上，它能抑制致病事件——p210 bcr-abl酪氨酸激酶，并使克隆性髓系祖细胞发生凋亡。在此，我们证明STI571还可通过激活Chk2-Cdc25A-Cdk2轴诱导生长停滞，这是一条在激活G(1)/S细胞周期检查点方面与p53互补的信号通路。体外将转导温度敏感型p210 bcr-abl构建体的32D小鼠髓系祖细胞克隆暴露于STI571，会导致Chk2磷酸化和激活、Cdc25A降解以及持续的Cdk2抑制性磷酸化，进而阻止细胞进入细胞周期的S期并在整个S期进展。Chk2和Cdc25A都是一个复杂网络的组成部分，该网络整合了参与调控细胞周期进展、DNA修复以及细胞生死抉择的信号。Chk2基因突变或表达降低，导致其蛋白对Cdc25A靶点失去功能，以及Cdc25A过表达，均与人类癌症的不良预后相关。在慢性粒细胞白血病中，它们可能会进一步增强克隆性髓系祖细胞的增殖优势和基因组不稳定性，这类患者预后较差，最终会对STI571产生耐药性。
