Michelle LeBeau, PhD
2014 Grant Recipient
Synergistic Interaction of the Microenvironment with del(5q) MDS Stem Cells
Basic Science Research Grant 2014
Hematopoiesis – the process of blood cell production – occurs in the bone marrow, and results from a complex interplay of blood stem cells and the bone marrow microenvironment or “niche”. For many years, scientists have known that the niche is comprised of a heterogeneous population of cells, also referred to as stroma, that provides a three-dimensional surface, or meshwork, that supports the normal development of stem cells into red blood cells, which carry oxygen throughout the body, and white blood cells, which normally fight infections.
The myelodysplastic syndromes (MDS) are a disorder of hematopoiesis, and include a spectrum of clonal hematopoietic stem cell disorders that are characterized by ineffective blood cell production and decreases in one or more types of blood cells, altered morphology, and a variable propensity to transform to leukemia. There is wide variation in the clinical course of MDS, and accurate predictions of disease course are essential as treatment strategies vary widely and are associated with dramatically different risks and side effects. At present, there is an urgent need to improve treatment outcomes for this patient population. An improved understanding of the biologic basis of MDS holds substantial potential for the development of rationally designed, more effective therapies with reduced side effects.
Our understanding of the etiology of MDS is incomplete. Growing evidence suggests that alterations of the microenvironment occur early, and play a pivotal role in the development of MDS by promoting the expansion of hematopoietic stem cells that have acquired complementary genetic changes. Thus, we view MDS as a unique disease of the “tissue”, rather than of blood cells alone. Recently, we showed that disruption of a particular gene (Apc) in the supporting niche cells leads to the development of MDS with ineffective production of red blood cells and anemia in mice. We also know that loss of Apc deregulates a specific mode of communication between niche cells and hematopoietic stem cells that is thought to be of particular importance in blood production, making this communication pathway of great interest for the development of MDS. During this project, we demonstrated that deregulation of this communication mode promotes the development of MDS, and that inhibiting this pathway using genetic methods or pharmacological drugs prevents the development of MDS. These findings raise the possibility that mitigation of bone marrow microenvironment defects may provide a novel target for treatment and prevention of MDS. In this regard, we have generated novel and tractable mouse models, which are available for preclinical studies of new candidate therapies for MDS researchers supported by the EPEF, and the scientific community at large.
Stoddart A, Wang J, Hu C, Fernald AA, Davis EM, Cheng JX, Le Beau MM, Cytotoxic Exposure to Both Hematopoietic Stem and Progenitor Cells and the Bone Marrow Niche Cooperate to Promote Leukemogenesis in a Mouse Model of Therapy-Related Myeloid Neoplasms with a del(5q), Blood 126(23): 2015.
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