A Silent Bone Marrow Shift May Predict Leukemia Years Before It Starts

Inflammation covertly rewires the bone marrow, enabling mutated stem cells to rise and setting the stage for future blood disease.

• Scientists from EMBL, University Medical Center Mainz (UMC Mainz), and the Department of Biomedicine in Basel have discovered that chronic inflammation can quietly reshape the bone marrow environment where blood stem cells live, years before leukemia develops.
• In a study published in Nature Communications, the team analyzed bone marrow samples from people with clonal hematopoiesis (CHIP) and myelodysplastic syndrome (MDS), revealing how inflammation helps drive the early steps of disease progression.
• As CHIP and MDS advance, key support cells that normally help blood stem cells function are gradually lost. These healthy cells are replaced by inflammatory support cells that become increasingly dominant and create a self-sustaining cycle of inflammation that interferes with normal blood production.
• The findings suggest that these inflammatory support cells play a central role in damaging the bone marrow at very early stages of disease, pointing to new treatment strategies that could slow or prevent the transition from blood disorders to cancer.

Every second, the bone marrow generates millions of new blood and immune cells. This constant output depends on close coordination among hematopoietic stem cells (HSCs), stromal support cells, and immune signaling systems that regulate growth and balance.

As the body ages, this coordination becomes easier to disrupt. Aging, long-lasting inflammation, or somatic mutations can interfere with how these cells communicate. When that happens, normal stem-cell renewal slows and mutated HSCs can quietly multiply. Over time, this leads to clonal hematopoiesis of indeterminate potential (CHIP), a condition found in about 10 to 20% of adults over age 60 and nearly 30% of those over 80.

CHIP usually causes no symptoms, but its impact is far from harmless. The condition raises the risk of blood cancers by tenfold and doubles the risk of cardiovascular disease and early death. A related disorder, myelodysplastic syndrome (MDS), involves faulty blood-cell production and gradual failure of the bone marrow. MDS affects up to 20 in every 100,000 people over age 70, and roughly 30% of cases progress to acute myeloid leukemia (AML), an aggressive and often fatal cancer.

Even with these serious outcomes, scientists have struggled to understand how changes in the bone marrow environment itself contribute to the development of these diseases.

Tracking How Mutated Stem Cells Gain an Advantage

To investigate how mutated HSCs begin to dominate, an international research team co-led by Judith Zaugg from EMBL and University of Basel and Borhane Guezguez from UMC Mainz carried out detailed molecular and spatial analyses of human bone marrow. The samples came from the BoHemE cohort study, conducted in collaboration with Uwe Platzbecker at the National Center for Tumor Diseases (NCT) Dresden.

The researchers used single-cell RNA sequencing, biopsy imaging, proteomics, and functional co-culture experiments to assemble a high-resolution picture of the bone marrow microenvironment. Their analysis included healthy donors, individuals with CHIP, and patients diagnosed with MDS. This approach revealed a major cellular shift that begins long before disease becomes clinically apparent. In place of the usual mesenchymal stromal cells (MSC) that support stem cells, the team found a growing population of inflammatory stromal cells.

“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.

These inflammatory MSCs (iMSC) behave very differently from their healthy counterparts. They release high levels of interferon-induced cytokines and chemokines, which draw in interferon-responsive T cells and activate them. Once engaged, these T cells intensify the inflammatory response. The result is a self-reinforcing cycle that maintains chronic inflammation, interferes with normal blood formation, and drives changes in blood vessels within the marrow.

What Fuels Inflammation Inside the Bone Marrow

One of the study’s more unexpected findings was what did not appear to cause the inflammation. The researchers found no evidence that mutated hematopoietic cells in MDS directly initiate the inflammatory process. This distinction became clear through the use of SpliceUp, a computational tool developed by co-lead author and EMBL alumnus Maksim Kholmatov together with Pedro Moura and Eva Hellström-Lindberg from Karolinska Institute. SpliceUp separates mutated and non-mutated cells in single-cell datasets by identifying abnormal RNA-splicing patterns. In MDS, the inflammatory network in the surrounding microenvironment overtakes much of the bone marrow’s normal regenerative framework.

“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.”

Targeting the Bone Marrow Microenvironment

Together, these findings place inflammation at the center of the earliest stages of blood disease. They also identify the bone marrow microenvironment (also referred to as the bone marrow niche) as a promising target for treatment. By shifting focus away from mutated stem cells alone and toward the cellular environment that supports them, the research points to new ways to prevent or slow disease progression.

Therapies that reduce inflammation or adjust interferon signaling could help preserve bone marrow function in older adults with CHIP. In addition, combining targeted drugs with treatments aimed at the microenvironment may help prevent progression to MDS or AML. The unique molecular patterns found in iMSCs and interferon-responsive T cells could also serve as early warning markers, identifying people at risk long before symptoms appear.

“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 Its Broader Implications

The implications extend beyond blood disorders. The study also adds to growing evidence around ‘inflammaging,’ the chronic, low-grade inflammation linked to many age-related conditions, including cancer as well as cardiovascular and metabolic disease. The bone marrow, long viewed only as a blood-producing organ, now appears to play an active role in driving systemic inflammatory aging. By clarifying how immune and stromal cells interact locally, the findings offer a framework for studying inflammatory remodeling in other myeloid cancers 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 research was published alongside a complementary study focused on the MDS bone marrow microenvironment, also appearing in Nature Communications and led by Marc Raaijmakers from Erasmus MC Cancer Institute in Rotterdam. Together, the two studies provide a broader picture of how inflammatory remodeling unfolds during the earliest stages of bone marrow disease.

References:

“Inflammatory stromal and T cells mediate human bone marrow niche remodeling in clonal hematopoiesis and myelodysplasia” by Karin D. Prummel, Kevin Woods, Maksim Kholmatov, Eric C. Schmitt, Evi P. Vlachou, Mayssa Labyadh, Rebekka Wehner, Gereon Poschmann, Kai Stühler, Susann Winter, Uta Oelschlaegel, Manja Wobus, Logan S. Schwartz, Pedro L. Moura, Eva Hellström-Lindberg, Krishnaraj Rajalingam, Matthias Theobald, Jennifer J. Trowbridge, Clémence Carron, Thierry Jaffredo, Marc Schmitz, Uwe Platzbecker, Judith B. Zaugg and Borhane Guezguez, 18 November 2025, Nature Communications.
DOI: 10.1038/s41467-025-65803-y

“An inflammatory T-cell-stromal axis contributes to hematopoietic stem/progenitor cell failure and clonal evolution in human myelodysplastic syndrome” by Lanpeng Chen, Yujie Bian, Eline Pronk, Claire van Dijk, Tim V.D. van Tienhoven, Remco M. Hoogenboezem, Eric M. Bindels, Dennis Bosch, Sadaf Fazeli, Aniek O. de Graaf, Theresia M. Westers, Maksim Kholmatov, Judith B. Zaugg, Pedro L. Moura, Eva Hellström-Lindberg, Arjan A. van de Loosdrecht, Joop H. Jansen, Mathijs A. Sanders and Marc H.G.P. Raaijmakers, 18 November 2025, Nature Communications.
DOI: 10.1038/s41467-025-65802-z

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.

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