Analysis of CNS-ALL cell biology using PDX model and development of new therapeutic strategy

Abstract

Central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) has been considered as a feature of high-risk disease. Although this risk is mitigated by current intended CNS-directed treatments based on risk stratification strategies, currently 10% or more of children will die from relapsing or unresponsive ALL. CNS-directed treatments are effective; however, they do not specifically target CNS leukemic cells and are associated with both serious short-term toxicities and debilitating long-term morbidities. Understanding the biology of ALL cells that lodge in the CNS may lead to the development of drugs that specifically target them, and this could further improve outcomes with fewer complications. Using patient samples and patient-derived xenograft (PDX) models, we found that CNS-derived leukemic cells had transcriptional signatures indicative of physiological adaptation to hypoxic microenvironments, and VEGFA is one of the most up-regulated genes in CNS-derived leukemic cells. An in vivo preclinical assay showed that VEGFA could be targeted to treat patients with ALL and who have CNS involvement. We are now focusing on a therapeutic strategy against CNS leukemia using CART cells. These observations may be useful for not only further mechanistic research, but also future clinical trials.