Bioengineering Leukemic Bone Marrow Niche for Dissecting the Heterogeneous Leukemia Chemo-resistance Mechanisms

B细胞急性淋巴细胞性白血病(B-ALL)是儿童最常见的癌症。当我们的骨髓开始产生未成熟的白细胞(称为淋巴母细胞)，而不是我们的身体抵御感染和疾病所需的成熟的白细胞时，就会发生B-ALL。近年来，随着多种药物化疗的进行，B-ALL患者的存活率显著提高，但它仍然是儿童癌症相关死亡的主要原因。与实体瘤相比，由于目前体外(实验室)和体内(体内)系统的限制，对白血病骨髓生态位的全面了解仍处于起步阶段。该项目将设计一种独特的人类白血病骨髓生态位模型，以研究化疗耐药的关键机制。通过高中、本科和研究生培训和外展活动，实践软光刻教育模块，以及新兴生物医学研究领域的夏季研讨会，将研究和教育整合在一起，以鼓励更多的年轻学生在科学和工程方面学习。该项目的目标是开发一个基于微流体的三维人类‘芯片上的白血病’平台，以概括体内骨髓组织结构和免疫，以剖析化疗中不同类型的白血病利基相关耐药机制。这个仿生的白血病骨髓生态位模型将采用实时成像、免疫细胞因子测量以及对造血、血管周围、骨内基质和细胞外低氧信号的精确控制。本研究旨在应用独特的器官型微生理学系统来(1)询问基质细胞如何通过劫持CXCL12/CXCR4、VLA-4/VCAM-1和NF-κB信号来差异调节B-ALL的生存和化疗耐药；(2)通过精确控制输入免疫细胞群和原位细胞因子监测来设计白血病骨髓免疫生态位，以确定导致B-ALL耐药的关键免疫调节因素；(3)评估不同亚型B-ALL样本的化疗疗效，并区分和共靶向骨髓生态位信号以改善化疗结果。这种组织工程白血病芯片模型可以进一步转化为B-ALL患者来源的样本，并可能转化为临床试验，以进行可靠的临床前测试，为更广泛的白血病患者优化和个性化化疗。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

B-cell acute lymphoblastic leukemia (B-ALL) is the most common cancer found in children. B-ALL occurs when our bone marrow, which is responsible for producing red and white blood cells, starts making immature white blood cells (termed lymphoblasts) instead of the mature white blood cells our body needs to defend against infection and disease. In recent years, B-ALL patient survival has improved dramatically with multi-drug chemotherapy treatments, but it remains a leading cause of cancer-related deaths in children. Compared to solid tumors, a comprehensive understanding of the leukemic bone marrow niche remains in infancy due to the limitations of current in vitro (in lab) and in vivo (in living) systems. This project will engineer a unique human leukemic bone marrow niche model to study critical mechanisms underlying chemotherapy resistance. Research and education are integrated through high school, undergraduate, and graduate training and outreach activities, a hands-on soft lithography educational module, and a summer workshop on emerging biomedical research areas, so as to encourage more young students to pursue studies in science and engineering.The goal of this project is to develop a microfluidics-based, three-dimensional human ‘Leukemia-on-a-Chip’ platform to recapitulate the in vivo bone marrow tissue architecture and immunity in order to dissect the heterogeneous leukemia niche associated resistance mechanisms in chemotherapy. This biomimetic leukemic bone marrow niche model will be engineered with real-time imaging, immune cytokine measurement, and precise control over the hematopoietic, perivascular, endosteal stromal niche and extracellular hypoxia signatures. This study aims to apply the unique organotypic microphysiological system to (1) Interrogate how the stromal niche cells differentially regulate B-ALL survival and chemo-resistance through hijacked CXCL12/CXCR4, VLA-4/VCAM-1, and NF-κB signaling; (2) Engineer the leukemic bone marrow immune niche with precise control over input immune cell populations and in situ cytokine monitoring to identify critical immune regulatory factors that underlie B-ALL chemo-resistance; (3) Assess chemotherapy efficacy for different subtypes of B-ALL samples and to distinguish and co-target the bone marrow niche signals to improve chemotherapy outcomes. Such a tissue engineered Leukemia-on-a-Chip model can be further translated to B-ALL patient-derived samples and, potentially, clinical trials for reliable preclinical tests to optimize and personalize chemotherapies for a broader population of leukemia patients.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.