Yuan Ruoshi, Zhu Xiaomei, Radich Jerald P, Ao Ping
Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.
Sci Rep. 2016 Apr 21;6:24307. doi: 10.1038/srep24307.
Acute promyelocytic leukemia (APL) remains the best example of a malignancy that can be cured clinically by differentiation therapy. We demonstrate that APL may emerge from a dynamical endogenous molecular-cellular network obtained from normal, non-cancerous molecular interactions such as signal transduction and translational regulation under physiological conditions. This unifying framework, which reproduces APL, normal progenitor, and differentiated granulocytic phenotypes as different robust states from the network dynamics, has the advantage to study transition between these states, i.e. critical drivers for leukemogenesis and targets for differentiation. The simulation results quantitatively reproduce microarray profiles of NB4 and HL60 cell lines in response to treatment and normal neutrophil differentiation, and lead to new findings such as biomarkers for APL and additional molecular targets for arsenic trioxide therapy. The modeling shows APL and normal states mutually suppress each other, both in "wiring" and in dynamical cooperation. Leukemogenesis and recovery under treatment may be a consequence of spontaneous or induced transitions between robust states, through "passes" or "dragging" by drug effects. Our approach rationalizes leukemic complexity and constructs a platform towards extending differentiation therapy by performing "dry" molecular biology experiments.
急性早幼粒细胞白血病（APL）仍然是临床上可通过分化疗法治愈的恶性肿瘤的最佳范例。我们证明，APL可能源自一个动态的内源性分子细胞网络，该网络由正常的、非癌性的分子相互作用产生，如生理条件下的信号转导和翻译调控。这个统一的框架将APL、正常祖细胞和分化的粒细胞表型再现为网络动力学中的不同稳定状态，具有研究这些状态之间转变的优势，即白血病发生的关键驱动因素和分化靶点。模拟结果定量地再现了NB4和HL60细胞系对治疗和正常中性粒细胞分化的微阵列谱，并得出了新的发现，如APL的生物标志物和三氧化二砷治疗的额外分子靶点。该模型显示，APL和正常状态在“连接”和动态协作方面相互抑制。白血病的发生和治疗后的恢复可能是通过药物效应的“传递”或“拉动”，在稳定状态之间自发或诱导转变的结果。我们的方法使白血病的复杂性合理化，并构建了一个通过进行“虚拟”分子生物学实验来扩展分化疗法的平台。
