Project 3: Modeling Malignant Myelopoiesis to Increase Efficacy of Targeted Leukemia Therapy

项目3摘要 慢性粒细胞白血病（CML）是最普遍的人类白血病之一，是一种天然的白血病模型。 由BCR-ABL 1酪氨酸激酶驱动的粒细胞生成失调。而酪氨酸激酶抑制剂 （TKI）如伊马替尼显著改善了CML的预后，需要终身治疗， 对医疗保健系统的相应的巨大经济影响。两个最大的未解决的问题， CML治疗学领域是了解对TKI治疗的原发性耐药的机制， 确定提高TKI停药后患者保持分子缓解率的策略 治疗，可能代表疾病的永久治愈。这个项目的科学前提是， 对CML的生物学及其对治疗的反应的临床相关见解可以通过更多的 疾病的生理学精确数学模型。该项目的第一个目标将利用UCI的 在复杂生物现象的数学建模方面拥有丰富的专业知识， CML的模型，包括生理相关的稳态反馈和前馈调节 正常细胞和白血病细胞之间的相互作用，以及干细胞和更分化的细胞之间的相互作用。最优 模型结构将通过基于机器的自动化模型选择过程进行审查，以获得模型 维持适当的稳定性和体内平衡，在生理上对压力和 不同的细胞室，并符合有限的现有定性数据的CML造血 来源于小鼠模型和患者研究。在第二个目标中，创新的二元BCR-ABL 1转基因 小鼠模型将首次用于确定控制生产的相关参数， CML中的恶性血细胞。正常和恶性造血细胞的单细胞转录组分析 干/祖细胞群体，包括异质多潜能祖细胞区室，将产生 关于CML骨髓生成异质性的重要新知识，并提供了对分子生物学的深入了解。 反馈/前馈调节机制。基于这些临床前研究，一项新的临床试验， 将开始深入了解CML患者中类似的细胞动力学参数。在最后的目标，某些 将在转基因小鼠模型中测试来自经验证的数学模型的预测。中 可以直接测试的假设是，白血病干细胞的原始负荷决定了白血病细胞的生长。 对TKI治疗初始反应和代表重要的预后因素， 刺激白血病干细胞周期进入最好是间歇地而不是连续地递送。 从建模工作中出现的其他假设将在赠款的第3-5年进行测试。统称 本项目中提出的研究将提供有关CML发病机制的重要新知识， 治疗策略，并为未来的CML干预性临床试验奠定基础。

Project 3 Summary Chronic myeloid leukemia (CML), one of the most prevalent of human leukemias, is a natural model of dysregulated granulopoiesis driven by the BCR-ABL1 tyrosine kinase. Whereas tyrosine kinase inhibitors (TKIs) such as imatinib have dramatically improved the prognosis in CML, lifelong treatment is needed, with a corresponding large economic impact on the health care system. The two biggest unaddressed questions in the field of CML therapeutics are to understand the mechanism of primary resistance to TKI therapy, and to identify strategies to increase the rate that patients remain in molecular remission after discontinuation of TKI therapy, possibly representing permanent cure of the disease. The Scientific Premise of this Project is that new and clinically relevant insights into the biology of CML and its response to therapy can be gained by a more physiologically accurate mathematical model of the disease. The first Aim of this Project will leverage UCI's extensive expertise in mathematical modeling of complex biological phenomena to develop more sophisticated models of CML that incorporate physiologically relevant homeostatic feedback and feedforward regulatory interactions between normal and leukemic cells, and between stem cells and more differentiated cells. Optimal model structures will be vetted by a machine-based automated model selection process to arrive at a model that maintains appropriate stability and homeostasis, responds physiologically to stress and depletion of different cell compartments, and conforms to the limited existing qualitative data on CML hematopoiesis derived from mouse models and patient studies. In the second Aim, an innovative binary BCR-ABL1 transgenic mouse model will be used to determine for the first time the relevant parameters governing the production of the malignant blood cells in CML. Single-cell transcriptome analysis of normal and malignant hematopoietic stem/progenitor populations, including the heterogeneous multi-potential progenitor compartment, will generate important new knowledge about the heterogeneity of CML myelopoiesis and provide insight into the molecular mechanisms of feedback/feedforward regulation. Based on these preclinical studies, a novel clinical trial to gain insight into similar cell kinetic parameters in CML patients will be initiated. In the final Aim, certain predictions from the validated mathematical model will be tested in the transgenic mouse model. Among the hypotheses that can be tested straightaway are that the original burden of leukemic stem cells governs the initial response to TKI therapy and represents and important prognostic factor, and that treatments that stimulate leukemic stem cell cycle entry are optimally delivered intermittently rather than continuously. Additional hypotheses emerging from the modeling effort will be tested in years 3-5 of the grant. Together, the studies proposed in this Project will provide critical new knowledge about the pathogenesis of CML, inform new therapeutic strategies, and set the stage for future interventional clinical trials in CML.