Over the years, this balance becomes vulnerable. Aging, chronic inflammation, or somatic mutations can disrupt communication among these cell groups, reducing normal stem-cell renewal and allowing mutated HSCs to expand unnoticed. This process leads to clonal hematopoiesis of indeterminate potential (CHIP), which appears in about 10 to 20% of adults over 60 and nearly 30% of those over 80.

Although people with CHIP typically have no symptoms, the condition increases the risk of blood cancers by tenfold and doubles the likelihood of cardiovascular disease and early death. Myelodysplastic syndrome (MDS), a related disorder involving clonal HSCs, causes inefficient blood-cell production and gradual failure of the bone marrow. It affects up to 20 in every 100,000 adults over 70, and around 30% of cases advance to acute myeloid leukemia (AML), an aggressive and often fatal cancer.

Despite the seriousness of these disorders, the contribution of the bone marrow microenvironment to their development has remained unclear.

Mapping Hidden Changes in the Bone Marrow Microenvironment

To better understand how mutated HSC clones gain dominance, an international research team co-led by Judith Zaugg from EMBL and University of Basel and Borhane Guezguez from UMC Mainz carried out an extensive molecular and spatial analysis of human bone marrow. The samples came from the BoHemE cohort study in collaboration with Uwe Platzbecker at the National Center for Tumor Diseases (NCT) Dresden.

Using single-cell RNA sequencing, biopsy imaging, proteomics, and co-culture models, the researchers created a detailed map of the bone marrow microenvironment in healthy donors (including those with CHIP) and in patients with MDS. Their analysis revealed an unexpected cellular shift that begins long before clinical signs appear. The team found that a population of inflammatory stromal cells gradually replaces the usual mesenchymal stromal cells (MSC) that support stem-cell function.

"I was surprised to observe such pronounced remodeling of the bone marrow microenvironment already in individuals with CHIP, although the underlying cause-and-effect relationships remain unclear," said Zaugg, co-senior author, EMBL Group Leader, and Professor at Basel University.

Unlike healthy stromal cells, these inflammatory MSCs (iMSC) produce large amounts of interferon-induced cytokines and chemokines. These molecules attract and activate interferon-responsive T cells, which then intensify the inflammatory activity. This creates a feed-forward loop that maintains chronic inflammation, disrupts normal blood formation, and contributes to vascular changes in the marrow.

Identifying What Drives Bone Marrow Inflammation

Interestingly, the researchers did not find signs that mutated hematopoietic cells in MDS directly trigger this inflammatory response. They were able to separate mutated from non-mutated cells using SpliceUp, a computational method developed by co-lead author and EMBL alumnus Maksim Kholmatov in collaboration with Pedro Moura and Eva Hellström-Lindberg from Karolinska Institute. SpliceUp identifies mutated cells in single-cell datasets by detecting abnormal RNA-splicing patterns. In MDS, the inflammatory network within the microenvironment becomes dominant and replaces much of the marrow's normal regenerative structure.

"Another striking observation was that MDS stem cells couldn't trigger stromal cells to produce CXCL12, an important signal that triggers blood cells to settle in the bone marrow. This failure may help explain why the bone marrow stops working properly," said Karin Prummel, co-lead author and EMBL postdoc.

"It was quite surprising to see the lack of a direct inflammatory effect that we could attribute to the mutant cells," said Maksim Kholmatov, co-lead author and EMBL alumnus. "However, when viewed in the context of changes in the T cell and stromal compartments, it underlines the importance of the bone marrow microenvironment in shaping disease progression."

Inflammation as an Early Driver of Blood Disease

These findings indicate that inflammation plays a central role in the earliest phases of disease and highlight the bone marrow microenvironment (also called the bone marrow niche) as a key therapeutic focus. By directing attention to the ecosystem that supports mutated stem cells rather than the mutated cells alone, the research points to new opportunities for early treatment and prevention.

Anti-inflammatory drugs or therapies that adjust interferon signaling may help preserve marrow function in older adults with CHIP. Combining targeted treatments with therapies that act on the microenvironment could slow or prevent the transition from CHIP to MDS or AML. The specific molecular features of iMSCs and interferon-responsive T cells may also serve as early biomarkers for people at elevated risk.

"Our findings reveal that the bone marrow microenvironment actively shapes the earliest stages of malignant evolution," said Guezguez, Principal Investigator in the Department of Hematology at UMC Mainz and co-senior author. "As advances in molecular profiling allow us to detect pre-leukemic states years before clinical onset, understanding how stromal and immune cells interact provides a foundation for preventive therapies that intercept disease progression before leukemia develops."

Inflammaging and the Wider Impact on Age-Related Disease

Beyond blood disorders, the results contribute to a broader understanding of 'inflammaging', the low-level, chronic inflammation that supports many age-related conditions, including cancer and cardiovascular and metabolic disease. The bone marrow, once considered only a site of blood production, now appears to be both affected by and responsible for systemic inflammatory aging. By showing how interactions between immune and stromal cells drive these changes, the study offers a model for exploring inflammatory remodeling in other myeloid malignancies and advanced leukemia.

"It will be crucial to study these processes over time; our current findings are based on cross-sectional data," Zaugg said. "This has important implications for therapies that replace malignant cells but leave the bone marrow niche intact, such as blood stem cell transplantation. We are now investigating to what extent the niche retains a 'memory' of disease, which could shape how it responds to new, healthy stem cells."

The work appears alongside a complementary study examining the MDS bone marrow microenvironment, also published in Nature Communications and led by Marc Raaijmakers from Erasmus MC Cancer Institute in Rotterdam. Together, the two studies offer a more complete view of inflammatory remodeling during the early phases of bone marrow disease.

The research involved collaborators from UMC Mainz, University of Basel, University Hospital Dresden, Karolinska Institute Sweden, The Jackson Laboratory USA, Sorbonne University, France, and DKTK partner institutions, including DKFZ and NCT Dresden. Funding came from the DKTK-CHOICE programme, the ERC grant EpiNicheAML to Judith Zaugg, the MCSA-funded ITN ENHPATHY, EMBO, Swiss National Foundation, and the José Carreras Leukämie-Stiftung.