Bone Marrow Microenvironment
Modeling of ALL and the Bone Marrow Microenvironment
Acute lymphoblastic leukemia (ALL) treatment regimens have dramatically improved the survival of ALL patients. However, chemoresistant minimal residual disease (MRD) that persists following cessation of therapy contributes to aggressive relapse. The bone marrow microenvironment (BMM) is an established “site of sanctuary” for ALL as well as myeloid lineage hematopoietic disease, with signals in this unique anatomical location contributing to drug resistance. Several models have been developed to recapitulate the interactions between the BMM and ALL cells. However, many in vitro models fail to accurately reflect the level of protection afforded to the most resistant sub-set of leukemic cells during co-culture with BMM elements. Pre-clinical in vivo models have advantages, but can be costly, and are often not fully informed by optimal in vitro studies. 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.
Image reference: Sergio P. Bydlowski, Debora Levy, Jorge M.L. Ruiz and Juliana Pereira (2013). Hematopoietic Stem Cell Niche: Role in Normal and Malignant Hematopoiesis, Stem Cell Biology in Normal Life and Diseases, Prof. Kamran Alimoghaddam (Ed.), ISBN: 978-953-51-1107-8, InTech, DOI: 10.5772/55508.