Inflammation rewires bone marrow microenvironment long before leukaemias develop

Every second of life, the bone marrow produces millions of new blood and immune cells. This continuous renewal relies on a delicate cooperation between hematopoietic stem cells (HSCs), supportive stromal cells, and immune regulators. 

Over time, this harmony becomes fragile. Ageing, persistent inflammation, or somatic mutations can distort the communication between these cellular partners, weakening stem-cell renewal and allowing silent expansion of mutated HSCs, leading to the development of clonal hematopoiesis of indeterminate potential (CHIP) that affects roughly 10 to 20% of adults over age 60, and nearly 30% over age 80. 

Although asymptomatic, CHIP increases the risk of blood cancers tenfold and doubles the risk of cardiovascular disease and premature death. Myelodysplastic syndrome (MDS), a related HSC clonal disorder, is marked by ineffective blood-cell production and progressive marrow failure. It affects up to 20 in 100,000 people over age 70, and as many as 30% of cases progress to acute myeloid leukaemia (AML), an aggressive, often fatal blood cancer.

Despite its clinical importance, how the bone marrow microenvironment contributes to these blood disorders has remained poorly understood.

To uncover how mutated HSC clones gain the upper hand, an international team co-led by Judith Zaugg from EMBL and University of Basel and Borhane Guezguez from UMC Mainz, conducted an in-depth molecular and spatial analysis of human bone marrow collected through the BoHemE cohort study in collaboration with Uwe Platzbecker at the National Center for Tumor Diseases (NCT) Dresden. 

Observing the stem-cell microenvironment

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 patients with MDS. This comprehensive approach revealed a striking cellular transformation that begins well before clinical disease appears. The investigators identified a population of inflammatory stromal cells that replace the normal, stem-cell-supportive mesenchymal stromal cells (MSC). 

“I was surprised to observe such pronounced remodelling 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) release large amounts of interferon-induced cytokines and chemokines that attract and activate interferon-responsive T cells. These T cells, in turn, amplify the inflammatory signal, creating a feed-forward loop that sustains chronic inflammation, suppresses healthy blood formation, and promotes vascular remodelling. 

Studying the drivers of bone marrow inflammation

Interestingly, the scientists did not find evidence that the mutated hematopoietic cells in MDS themselves drive this inflammation. They could make this distinction using a new computational tool, SpliceUp, developed by Maksim Kholmatov, co-lead author and EMBL alumnus, in collaboration with Pedro Moura and Eva Hellström-Lindberg from Karolinska Institute. The tool can distinguish mutated from non-mutated cells within single-cell data based on aberrant RNA-splicing patterns. In MDS, this inflammatory network in the microenvironment becomes dominant, replacing much of the bone marrow’s regenerative architecture.

“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.”

The discovery positions inflammation as a central force in the earliest stages of blood disease and establishes the bone marrow microenvironment (also referred to as the bone marrow niche) as a critical therapeutic target. By shifting attention from mutated stem cells to the cellular ecosystem that sustains them, the research opens the door to new preventive and therapeutic strategies. 

Anti-inflammatory or interferon-modulating agents may preserve bone marrow function in older adults with CHIP, while rational combinations of targeted drugs and microenvironment-directed therapies could halt progression to MDS or AML. The distinct molecular signatures of iMSCs and interferon-responsive T cells may also serve as biomarkers to identify individuals at risk long before clinical symptoms emerge.

“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 leukaemia develops.”

A new framework for understanding inflammatory remodelling

Beyond haematology, the work broadens understanding of ‘inflammaging,’ the chronic, low-grade inflammation that underpins many age-related disorders – from cancer to cardiovascular and metabolic disease. The bone marrow, once viewed purely as a site of blood production, now appears as both a target and a driver of systemic inflammatory ageing. By revealing how local immune-stromal interactions fuel disease, this study provides a new framework for investigating inflammatory remodelling in other myeloid malignancies and advanced leukaemia.

“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 is published back-to-back with a complementary study on the MDS bone marrow microenvironment, also published in the journal Nature Communications and led by Marc Raaijmakers from Erasmus MC Cancer Institute in Rotterdam. The two studies together provide a broader view of inflammatory remodelling across early stages of bone marrow disease.

The study was conducted in collaboration with 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, with funding 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.