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Inflammation rewires the bone marrow microenvironment long before leukemias develop (Zaugg Lab)
The bone marrow continuously produces new blood and immune cells through coordinated signals between stem cells, stromal cells, and immune regulators. Aging, inflammation, or mutations can disrupt this balance, allowing mutated stem cells to expand silently and leading to clonal hematopoiesis of indeterminate potential (CHIP), which becomes common in older adults and increases the risk of blood cancers and cardiovascular disease. A related disorder, myelodysplastic syndrome (MDS), causes ineffective blood production and bone-marrow failure, and can progress to acute myeloid leukemia.
To uncover how mutated HSC clones outcompete normal HSCs, an international team with collaborators across Europe and the US, co-led by Judith Zaugg (DBM/EMBL) and Borhane Guezguez (UMC Mainz), performed an in-depth molecular and spatial analysis of human bone marrow through the BoHemE cohort study, in collaboration with Uwe Platzbecker (NCT Dresden). Using single-cell RNA sequencing, biopsy imaging, proteomics, and functional co-culture models, the researchers built a high-resolution map of the bone marrow microenvironment across healthy donors (including those with CHIP) and MDS patients. They observed a striking cellular transformation that begins long before clinical disease: healthy mesenchymal stromal cells (MSC) are replaced by inflammatory MSCs (iMSC). “I was surprised to observe such pronounced remodeling of the bone marrow microenvironment already in individuals with CHIP,” said Zaugg. Unlike healthy stromal cells, iMSCs release interferon-induced cytokines and chemokines that attract interferon-responsive T cells. These T cells amplify the inflammatory signal, creating a feed-forward loop that sustains chronic inflammation, suppresses healthy blood formation, and promotes vascular remodeling.
The scientists did not find evidence that mutated hematopoietic cells in MDS themselves drive this inflammation. Using a new computational tool, SpliceUp, developed by Maksim Kholmatov, they distinguished mutated from non-mutated cells based on aberrant RNA-splicing patterns. “It was quite surprising to see the lack of a direct inflammatory effect attributable to mutant cells,” Kholmatov said. In MDS, stem cells fail to induce stromal cells to produce CXCL12, a key signal required for blood-cell homing. This mechanism may contribute to the collapse of bone marrow function. The bone marrow microenvironment thus actively shapes the earliest stages of malignant evolution. As early detection of pre-leukemic states improves, understanding stromal–immune interactions offers a foundation for preventive therapies. Anti-inflammatory or interferon-modulating agents may preserve bone-marrow function in older adults with CHIP, while targeted therapies combined with microenvironment-directed interventions could halt progression to MDS or AML. Distinct molecular signatures of iMSCs and interferon-responsive T cells may also serve as early-risk biomarkers.
Beyond hematology, the work strengthens the concept of “inflammaging,” highlighting the bone marrow as both a target and driver of systemic inflammatory aging. “It will be crucial to study these processes over time,” Zaugg said, noting implications for therapies like stem-cell transplantation, where the niche may retain a “memory” of disease. A complementary study, led by Marc Raaijmakers (Erasmus MC), is published back-to-back in Nature Communications, together providing a broader view of inflammatory remodeling in early bone-marrow disease.
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