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

点击翻译按钮获取中文摘要

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.