Dong-Feng Zeng, Ting Liu, Yong Zhang, Cheng Chang, Xi Zhang, Pei-Yan Kong
Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
Pathol Oncol Res. 2014 Apr;20(2):309-17. doi: 10.1007/s12253-013-9696-z. Epub 2013 Oct 2.
Accumulating evidence indicates that the interaction of human LSCs (leukemic stem cells) with the hematopoietic microenvironment, mediated by the thrombopoietin (TPO)/c-MPL pathway, may be an underlying mechanism for resistance to cell cycle-dependent cytotoxic chemotherapy. However, the role of TPO/c-MPL signaling in AML (acute myelogenous leukemia) chemotherapy resistance hasn't been fully understood. The c-MPL and TPO levels in different AML samples were measured by flow cytometry and ELISA. We also assessed the TPO levels in the osteoblasts derived from bone mesenchymal stem cells (BMSCs). The survival rate of an AML cell line that had been co-cultured with different BMSC-derived osteoblasts was measured to determine the IC50 of an AML chemotherapy drug daunorubicin (DNR). The levels of TPO/c-MPL in the initial and relapse AML patients were significantly higher than that in the control (P < 0.05). The osteoblasts derived from AML patients' BMSCs secreted more TPO than the osteoblasts derived from normal control BMSCs (P < 0.05). A strong positive correlation between the TPO level and c-MPL expression was found in the bone marrow mononuclear cells of the relapse AML patients. More importantly, the IC50 of DNR in the HEL + AML-derived osteoblasts was the highest among all co-culture systems. High level of TPO/c-MPL signaling may protect LSCs from chemotherapy in AML. The effects of inhibition of the TPO/c-MPL pathway on enhancing the chemotherapy sensitivity of AML cells, and on their downstream effector molecules that direct the interactions between patient-derived blasts and leukemia repopulating cells need to be further studied.
越来越多的证据表明，人类白血病干细胞（LSCs）与造血微环境之间的相互作用，由血小板生成素（TPO）/c-MPL途径介导，可能是对细胞周期依赖性细胞毒性化疗产生耐药性的潜在机制。然而，TPO/c-MPL信号在急性髓系白血病（AML）化疗耐药中的作用尚未完全阐明。通过流式细胞术和酶联免疫吸附测定法（ELISA）测量不同AML样本中的c-MPL和TPO水平。我们还评估了源自骨髓间充质干细胞（BMSCs）的成骨细胞中的TPO水平。测量与不同BMSC来源的成骨细胞共培养的AML细胞系的存活率，以确定AML化疗药物柔红霉素（DNR）的半数抑制浓度（IC50）。初发和复发AML患者中TPO/c-MPL的水平显著高于对照组（P < 0.05）。AML患者BMSCs来源的成骨细胞比正常对照BMSCs来源的成骨细胞分泌更多的TPO（P < 0.05）。在复发AML患者的骨髓单个核细胞中发现TPO水平与c-MPL表达之间存在强正相关。更重要的是，在所有共培养体系中，HEL + AML来源的成骨细胞中DNR的IC50最高。高水平的TPO/c-MPL信号可能保护AML中的LSCs免受化疗影响。抑制TPO/c-MPL途径对增强AML细胞化疗敏感性及其下游效应分子的影响，这些效应分子指导患者来源的原始细胞与白血病再增殖细胞之间的相互作用，有待进一步研究。
