Thomas E K, Cancelas J A, Zheng Y, Williams D A
Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Leukemia. 2008 May;22(5):898-904. doi: 10.1038/leu.2008.71. Epub 2008 Mar 20.
Chronic myelogenous leukemia (CML) is a malignant disease characterized by expression of p210-BCR-ABL, the product of the Philadelphia chromosome. Survival of CML patients has been significantly improved with the introduction of tyrosine kinase inhibitors that induce long-term hematologic remissions. However, mounting evidence indicates that the use of a single tyrosine kinase inhibitor does not cure this disease due to the persistence of p210-BCR-ABL at the molecular level or the acquired resistance in the stem cell compartment to individual inhibitors. We have recently shown in a murine model that deficiency of the Rho GTPases Rac1 and Rac2 significantly reduces p210-BCR-ABL-mediated proliferation in vitro and myeloproliferative disease in vivo, suggesting Rac as a potential therapeutic target in p210-BCR-ABL-induced disease. This target has been further validated using a first-generation Rac-specific small molecule inhibitor. In this review we describe the role of Rac GTPases in p210-BCR-ABL-induced leukemogenesis and explore the possibility of combinatorial therapies that include tyrosine kinase inhibitor(s) and Rac GTPase inhibitors in the treatment of CML.
慢性粒细胞白血病（CML）是一种恶性疾病，其特征是表达费城染色体的产物p210-BCR-ABL。随着酪氨酸激酶抑制剂的引入，CML患者的生存率得到了显著提高，这些抑制剂可诱导长期血液学缓解。然而，越来越多的证据表明，由于p210-BCR-ABL在分子水平上的持续存在或干细胞区室对个别抑制剂产生获得性耐药，使用单一酪氨酸激酶抑制剂并不能治愈这种疾病。我们最近在小鼠模型中表明，Rho GTPases Rac1和Rac2的缺陷显著降低了p210-BCR-ABL介导的体外增殖和体内骨髓增殖性疾病，提示Rac作为p210-BCR-ABL诱导疾病的潜在治疗靶点。使用第一代Rac特异性小分子抑制剂进一步验证了该靶点。在这篇综述中，我们描述了Rac GTPases在p210-BCR-ABL诱导的白血病发生中的作用，并探讨了在CML治疗中联合使用酪氨酸激酶抑制剂和Rac GTPase抑制剂的可能性。
