While we know the genetic drivers of myelodysplastic syndromes (MDS), little is known about how those mutations arise in the bone marrow (BM) and drive the development of MDS. Interestingly, over the past decade, we and others have characterized clonal hematopoiesis (CH)—the presence of blood cancer-associated mutations in the peripheral blood (PB) of disease free individuals. While this likely pre-cancerous state leads to MDS, the specific steps driving that transformation are unknown. Moreover, all of our understanding of CH is based on studies of the PB and it is unknown if that reflects the BM process underlying CH. Even within the BM, the spatial distribution of CH clones is unknown, which has clinical implications when treatment decisions are made based on a small 3-4mm core BM biopsy.

To answer these questions, we have developed methods for spatially-aware mutation detection in the BM. In a pilot study, we characterized the BM of an individual with polycythemia vera—a myeloproliferative neoplasm. Surprisingly, we found striking spatial segregation of somatic mutations in the BM and a complex clonal organization by single-cell analysis. Here, we plan to use these tools to characterize the spatial and clonal distribution of CH in the BM of cancer-free adults. This will define how CH clones are organized in the BM and how their clonal dynamics can lead to MDS. Long-term this will inform efforts to develop interventions to prevent the transformation of CH into MDS.