Molecular Oncology Program, H. Lee Moffitt Cancer Center Tampa, FL, USA.
Front Oncol. 2012 Apr 10;2:30. doi: 10.3389/fonc.2012.00030. eCollection 2012.
Chronic myeloid leukemia (CML) is initially driven by the bcr-abl fusion oncoprotein. The identification of bcr-abl led to the discovery and rapid translation into the clinic of bcr-abl kinase inhibitors. Although, bcr-abl inhibitors are efficacious, experimental evidence indicates that targeting bcr-abl is not sufficient for elimination of minimal residual disease found within the bone marrow (BM). Experimental evidence indicates that the failure to eliminate the leukemic stem cell contributes to persistent minimal residual disease. Thus curative strategies will likely need to focus on strategies where bcr-abl inhibitors are given in combination with agents that specifically target the leukemic stem cell or the leukemic stem cell niche. One potential target to be exploited is the Janus kinase (JAK)/signal transducers and activators of transcription 3 (STAT3) pathway. Recently using STAT3 conditional knock-out mice it was shown that STAT3 is critical for initiating the disease. Interestingly, in the absence of treatment, STAT3 was not shown to be required for maintenance of the disease, suggesting that STAT3 is required only in the tumor initiating stem cell population (Hoelbl et al., 2010). In the context of the BM microenvironment, STAT3 is activated in a bcr-abl independent manner by the cytokine milieu. Activation of JAK/STAT3 was shown to contribute to cell survival even in the event of complete inhibition of bcr-abl activity within the BM compartment. Taken together, these studies suggest that JAK/STAT3 is an attractive therapeutic target for developing strategies for targeting the JAK-STAT3 pathway in combination with bcr-abl kinase inhibitors and may represent a viable strategy for eliminating or reducing minimal residual disease located in the BM in CML.
慢性髓性白血病（CML）最初由 bcr-abl 融合致癌蛋白驱动。bcr-abl 的鉴定导致了 bcr-abl 激酶抑制剂的发现和迅速转化为临床应用。尽管 bcr-abl 抑制剂是有效的，但实验证据表明，针对 bcr-abl 不足以消除骨髓（BM）中发现的微小残留疾病。实验证据表明，未能消除白血病干细胞是导致持续微小残留疾病的原因。因此，治愈策略可能需要集中在 bcr-abl 抑制剂与专门针对白血病干细胞或白血病干细胞龛的药物联合使用的策略上。一个潜在的目标是利用 Janus 激酶（JAK）/信号转导和转录激活因子 3（STAT3）途径。最近使用 STAT3 条件敲除小鼠表明，STAT3 对于疾病的发生至关重要。有趣的是，在没有治疗的情况下，STAT3 不需要维持疾病，这表明 STAT3 仅在肿瘤起始干细胞群体中是必需的（Hoelbl 等人，2010）。在 BM 微环境中，STAT3 通过细胞因子环境以 bcr-abl 非依赖性方式激活。即使在 BM 隔室中完全抑制 bcr-abl 活性的情况下，JAK/STAT3 的激活也被证明有助于细胞存活。总之，这些研究表明，JAK/STAT3 是开发针对 JAK-STAT3 途径的策略与 bcr-abl 激酶抑制剂联合使用的有吸引力的治疗靶点，并可能代表消除或减少 CML 中位于 BM 中的微小残留疾病的可行策略。
