Spatial Control of Myeloid Differentiation

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Abstract: Mounting evidence indicates that lineage decisions are controlled by local structures that support differentiation in distinct regions of the bone marrow. Our ability to manipulate hematopoiesis to treat disease has been hampered by our lack of understanding of these anatomical cues. We have found that HPC are regionally organized in the BM and that progenitors and immature cells belonging to the same lineage segregate to different sinusoids. We have also found that there is regional organization to CSF1 production and that specific BM vessels are critical sources of CSF1 that regulate MDP, monocytes and dendritic cells but not HSC or macrophages. The central hypothesis is that different subsets of sinusoids function as assembly lines or hubs that organize and maintain different hematopoietic lineages through the production of lineage-specific cytokines. We want to understand how these cellular assembly lines function in the steady-state and after perturbation by acute myeloid leukemia (AML). We will test this hypothesis in two aims. In Aim 1 we will determine the physiology of these assembly lines using clonal fate mapping in situ; identifying the components of each assembly line; and conditionally deleting specific cytokines from key components of each assembly line. In Aim 2 we will investigate how AML inhibits normal hematopoiesis by perturbing the microenvironment that supports each assembly line.