More Effective Treatments for Leukemia

Improvements in acute lymphoblastic leukemia (ALL) treatments have dramatically improved the survival of ALL patients, the majority of whom are children. However, chemoresistant minimal residual disease (MRD) that persists following cessation of therapy contributes to aggressive relapse. Understanding how to make leukemic cells more responsive to therapy is critical to truly eradicating disease and preventing recurrence that is often very difficult to treat. The bone marrow is the site where leukemia originates, and also the site where a subset of tumor cells “hide out” (a site of sanctuary) and survive during therapy and then reconstitute disease after the treatment is complete. Several models have been developed to recapitulate the interactions between the bone marrow cells that provide survival signals to tumor cells and the tumor cells themselves. However, many in vitro models fail to accurately reflect the level of protection afforded to the most resistant sub-set of leukemic We use an innovative extension of 2D co-culture wherein ALL cells uniquely interact with bone marrow derived stromal cells. Tumor cells in this model bury beneath primary human bone marrow derived stromal cells or osteoblasts, termed “phase dim” (PD) ALL, and exhibit a unique phenotype characterized by altered metabolism, distinct protein expression profiles, increased quiescence, and pronounced chemotherapy resistance. We investigate the PD subpopulation to model resistant leukemic disease to more efficiently inform pre-clinical design and investigation of MRD and relapse that arises from BMM supported leukemic tumor cells. These observations are important in the development on new therapies that are ideally more effective while being less harsh for the patient. This is particularly critical in children where the goal is not just to cure disease, but also to avoid long-term side effects that often accompany aggressive treatment.