A compartmentalized inflammatory landscape and macrophage plasticity regulate Tet2 +/− -mediated clonal hematopoiesis

ABSTRACT: Clonal hematopoiesis of indeterminate potential (CHIP) is driven by hematopoietic stem cells carrying leukemia-associated mutations that expand in the bone marrow. Several prior studies have revealed that the spatial organization of hematopoietic cells in the bone marrow affects clonal behaviors. Specifically, leukemic blasts have been found to expand almost exclusively in a subset of marrow cavities that are undergoing active bone remodeling, but whether these cavities also support the expansion of nonmalignant mutant clones has never been visualized. Although it is widely appreciated that systemic inflammation promotes the selection of mutant clones, this view has emerged without considering the potential heterogeneity in the inflammatory landscape shaped by local bone remodeling. Leveraging intravital imaging and a murine model of CHIP (Tet2+/-), we demonstrated transcriptional and functional compartmentalization of the marrow microenvironment. Macrophages within nonresorptive cavities are inherently anti-inflammatory, which suppresses disease-initiating Tet2+/- cells while preserving their healthy counterparts. Time-lapse imaging further revealed nontransient association between Tet2+/- clones and CD206+ macrophages. Spatially resolved single-cell transcriptomic profiling and functional assessment revealed that physiological bone remodeling influences CD206+ macrophage plasticity and cytokine secretion, which regulate the clonal burden. In addition, antitumor immunity alteration within the microenvironment occurred as early as the formation of initial clones. Suppressing bone remodeling with zoledronate or targeting macrophage-associated niche factors mitigated clonal development. Collectively, our study reveals a previously unrecognized inflammatory landscape shaped by local bone remodeling. The finding presents targetable mechanisms and warrants further studies on the use and precautions of bone-modulating management in clonal blood disorders.