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)是人类最常见的白血病之一，是一种自然的 由bcr-abl1酪氨酸激酶驱动的粒细胞生成失调。而酪氨酸激酶抑制剂 伊马替尼等TKI显著改善了CML的预后，需要终生治疗， 相应地对医疗保健系统造成较大的经济影响。中最大的两个未解决的问题 慢性粒细胞白血病的治疗领域是了解TKI治疗的原发耐药机制，并 确定提高患者在TKI停用后保持分子缓解率的策略 治疗，可能代表着这种疾病的根治。这个项目的科学前提是新的 对慢性粒细胞白血病生物学及其治疗反应的临床相关见解可以通过更多的 生理上准确的疾病数学模型。该项目的首要目标是利用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，以开发更复杂的 结合生理相关的稳态反馈和前馈调节的慢性粒细胞白血病模型 正常细胞和白血病细胞之间的相互作用，以及干细胞和更多分化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模型选择过程进行审查，以得出模型 保持适当的稳定性和动态平衡，在生理上对压力和能量消耗做出反应 不同的细胞室，符合现有关于CML造血的有限定性数据 源自小鼠模型和患者研究。在第二个目的中，创新的二元BCR-ABL1转基因 将首次使用鼠标模型来确定控制生产的相关参数 慢性粒细胞白血病中的恶性血细胞。正常和恶性血液病的单细胞转录组分析 干细胞/祖细胞群体，包括异质的多潜能祖细胞隔间，将产生 关于CML骨髓生成异质性的重要新知识，并提供了对分子水平的洞察 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 将开始深入了解CML患者中类似的细胞动力学参数。在最终的目标中，一定 来自经过验证的数学模型的预测将在转基因小鼠模型中进行测试。在这些人中 可以直接检验的假设是，白血病干细胞的原始负担支配着 对TKI治疗初始反应和代表的重要预后因素，以及治疗 刺激白血病干细胞周期进入的最佳方式是间歇输送，而不是连续输送。 建模工作中出现的其他假设将在拨款的第3-5年进行测试。团结在一起， 本项目中提出的研究将为CML的发病机制提供关键的新知识，为新的 治疗策略，并为CML未来的介入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.