Understanding the Impact of Clonal Hematopoiesis on Aging Human Bone Marrow - PROJECT SUMMARY/ABSTRACT Every year there are two million new cases of cancer diagnosed in the United States and 600,000 cancer-related deaths. Preventing the development of cancer, when therapies are more effective, is one of the most potent methods to decrease cancer-related mortality. While the acquired genomic drivers of cancer are known, it is less well understood how those genomic changes arise and drive tumorigenesis. Understanding this process may yield new interventions to prevent malignant transformation from these pre-malignant states. Interestingly, in the hematologic system, somatic mutations that drive leukemia can be detected at low levels in nearly all disease free adults—a phenomenon termed clonal hematopoiesis. Clonal hematopoiesis increases in prevalence with age and is associated with increased cancer risk. However, clonal hematopoiesis is so common that it rarely progresses to blood cancer and the factors driving leukemic transformation are largely unknown. This also occurs in other solid organs such as skin and esophagus where clonal mutations are spatially constrained in the tissue. Prior work has focused on understanding how clonal hematopoiesis arises and evolves over time in the peripheral blood of healthy individuals. Less is known about how these clones exist and interact within the bone marrow—the source of hematopoiesis in humans. It is possible that these clones remodel their local niche to support clonal evolution and leukemic transformation. Intriguingly, given the prevalence and age-dependence of clonal hematopoiesis, these changes may also negatively affect physiological function to drive aging-associated changes in the hematologic system (e.g. anemia and declining immunity). This proposal seeks to understand how these clones exist and interact within the aging human BM niche in cancer-free adults. This builds upon prior techniques developed for rare mutation detection, single-cell mutation characterization and immunophenotyping, and spatial mutation detection. In a pilot study of a patient with hematologic malignancy, applying these techniques demonstrated marked spatial and clonal heterogeneity within their bone marrow. Now these tools will be applied to examine clonal organization and heterogeneity within the bone marrow to study “healthy” aging hematopoiesis before blood cancer develops. This study is possible because of a unique collaboration with Mid-America Transplant, the regional organ procurement organization, to provide multiple bone marrow containing bones and peripheral blood from brain-dead organ/tissue donors for this study. This study has the potential to uncover how somatic mutation and aging conspire to drive hematologic dysfunction, support clone persistence for decades, and drive leukemogenesis directly in human specimens. The tools developed for this project are broadly applicable to future studies discovering how aging affects all of the organs within the human body. Long-term, this will identify potentially testable mechanisms to reduce the risk of malignant transformation and maintain homeostatic organ function late in life.
