By Hendra Lukman 
Every moment, the bone marrow diligently generates millions of fresh blood and immune cells. This continuous process, a cornerstone of our health, relies on a delicate and precisely orchestrated balance between hematopoietic stem cells (HSCs), the supportive stromal cells that create the cellular environment, and a complex network of immune signals. However, this vital equilibrium becomes increasingly vulnerable with age, chronic inflammation, or the accumulation of somatic mutations. These disruptions can impair communication among these cellular partners, leading to a decline in normal stem-cell renewal and, critically, allowing mutated HSCs to proliferate unchecked. This phenomenon gives rise to clonal hematopoiesis of indeterminate potential (CHIP), a condition observed in approximately 10% to 20% of adults over 60, and a staggering nearly 30% of those over 80.
While individuals with CHIP often remain asymptomatic, the condition carries significant risks. It amplifies the likelihood of developing blood cancers by tenfold and doubles the risk of cardiovascular disease and premature death. A related disorder, myelodysplastic syndrome (MDS), also involves clonal HSCs but is characterized by inefficient blood-cell production and a progressive failure of bone marrow function. Affecting up to 20 in every 100,000 adults over 70, MDS has a grim prognosis, with approximately 30% of cases advancing to acute myeloid leukemia (AML), an aggressive and often fatal cancer. Despite the profound seriousness of these conditions, the precise contribution of the bone marrow microenvironment – the intricate ecosystem that houses and supports blood-forming cells – to their development has remained an elusive puzzle.
Unraveling Hidden Changes: A Molecular and Spatial Map of the Bone Marrow Microenvironment
To shed light on how mutated HSC clones gain dominance within the bone marrow, an international consortium of researchers, co-led by Judith Zaugg from the European Molecular Biology Laboratory (EMBL) and the University of Basel, and Borhane Guezguez from the University Medical Center Mainz (UMC Mainz), embarked on an ambitious molecular and spatial analysis of human bone marrow. The study drew upon samples from the BoHemE cohort study, conducted in collaboration with Uwe Platzbecker at the National Center for Tumor Diseases (NCT) Dresden, a prominent German cancer research center.
Employing a sophisticated arsenal of techniques, including single-cell RNA sequencing to decipher the gene expression profiles of individual cells, biopsy imaging for spatial context, proteomics to analyze protein composition, and co-culture models to simulate cellular interactions, the researchers meticulously constructed a detailed map of the bone marrow microenvironment. This comprehensive analysis encompassed healthy donors, including those with CHIP, and patients diagnosed with MDS. The findings revealed a striking and unexpected cellular transformation that commences long before any overt clinical symptoms manifest. The team identified a gradual replacement of the typical mesenchymal stromal cells (MSCs), which are crucial for supporting stem-cell function, by a distinct population of inflammatory stromal cells.
Judith Zaugg, a co-senior author of the study and EMBL Group Leader and Professor at the University of Basel, expressed her surprise at the extent of these changes. "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," she stated. This observation suggests that the bone marrow’s internal environment undergoes significant alterations at very early stages of disease development, even before the emergence of observable health issues.
The Rise of Inflammatory Stromal Cells and a Vicious Cycle
Unlike healthy stromal cells, these newly identified inflammatory MSCs (iMSCs) exhibit a pronounced ability to produce large quantities of interferon-induced cytokines and chemokines. These signaling molecules act as potent attractants and activators for interferon-responsive T cells, a critical component of the immune system. Once activated, these T cells further intensify the inflammatory activity within the bone marrow. This creates a self-perpetuating, or feed-forward, loop that sustains chronic inflammation. This persistent inflammatory state disrupts the normal, healthy process of blood formation and contributes to detrimental vascular changes within the marrow.
The research team sought to understand the triggers of this inflammatory cascade. A key question was whether the mutated hematopoietic cells themselves directly instigated this inflammatory response. To address this, co-lead author Maksim Kholmatov, an EMBL alumnus, developed a sophisticated computational method called SpliceUp. In collaboration with Pedro Moura and Eva Hellström-Lindberg from the Karolinska Institute in Sweden, Kholmatov utilized SpliceUp to analyze single-cell datasets and identify mutated cells by detecting abnormal RNA-splicing patterns. This innovative approach allowed the researchers to effectively separate mutated cells from their non-mutated counterparts.
Their analysis yielded a significant finding: in MDS, the established inflammatory network within the microenvironment appears to become dominant, displacing much of the marrow’s normal regenerative structure. Crucially, the researchers did not find direct evidence that the mutated hematopoietic cells in MDS were the primary drivers of this inflammatory response.
Karin Prummel, a co-lead author and EMBL postdoc, highlighted another unexpected observation. "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," she explained. CXCL12 plays a vital role in guiding hematopoietic stem cells to their appropriate niches within the bone marrow and in maintaining their function. Its absence could lead to stem cells becoming misplaced or malfunctioning.
Maksim Kholmatov further elaborated on the significance of these findings. "It was quite surprising to see the lack of a direct inflammatory effect that we could attribute to the mutant cells," he remarked. "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." This perspective shifts the focus from solely targeting the mutated cells to understanding the broader cellular ecosystem in which they reside.
Inflammation as an Early Architect of Blood Disease Progression
The cumulative evidence from this research strongly indicates that inflammation plays a pivotal role in the very earliest phases of blood disorders. This revelation positions the bone marrow microenvironment, often referred to as the bone marrow niche, as a critical therapeutic target. By directing attention to the complex ecosystem that supports the proliferation of mutated stem cells, rather than focusing solely on the mutated cells themselves, this research opens up new avenues for early intervention and disease prevention.
The implications for treatment are profound. Anti-inflammatory drugs or therapies designed to modulate interferon signaling pathways could potentially help preserve bone marrow function in older adults who have CHIP. Furthermore, combining such targeted anti-inflammatory treatments with therapies that specifically act on the microenvironment might effectively slow down or even prevent the progression from CHIP to more aggressive conditions like MDS or AML. The distinct molecular signatures of iMSCs and interferon-responsive T cells identified in this study could also serve as valuable early biomarkers, enabling the identification of individuals at elevated risk for these diseases years before symptoms appear.
Borhane Guezguez, a Principal Investigator in the Department of Hematology at UMC Mainz and co-senior author, emphasized this point. "Our findings reveal that the bone marrow microenvironment actively shapes the earliest stages of malignant evolution," he stated. "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." This proactive approach to disease management holds the promise of significantly improving patient outcomes.
‘Inflammaging’ and the Broader Spectrum of Age-Related Diseases
The impact of these findings extends beyond the realm of blood disorders, contributing significantly to our understanding of ‘inflammaging.’ This term describes the low-level, chronic inflammation that is increasingly recognized as a contributing factor to a wide array of age-related conditions, including various cancers, cardiovascular diseases, and metabolic disorders. The bone marrow, once viewed primarily as a site of blood production, now appears to be both a recipient of and a contributor to systemic inflammatory aging.
By elucidating how the intricate interactions between immune cells and stromal cells within the bone marrow drive these age-related inflammatory changes, this study provides a compelling model for investigating similar inflammatory remodeling processes in other myeloid malignancies and in advanced stages of leukemia. This broader perspective suggests that interventions targeting the bone marrow microenvironment could have far-reaching benefits for overall healthspan and the management of age-related diseases.
Judith Zaugg highlighted the importance of longitudinal studies to further solidify these findings. "It will be crucial to study these processes over time; our current findings are based on cross-sectional data," she cautioned. This is particularly relevant for therapies that aim to replace malignant cells, such as blood stem cell transplantation, while leaving the bone marrow niche intact. "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." Understanding this potential "memory" effect could be critical for optimizing the success of transplantation and other regenerative therapies.
Complementing this groundbreaking research, a separate study that also examined the MDS bone marrow microenvironment was published concurrently in Nature Communications. This complementary work, led by Marc Raaijmakers from the Erasmus MC Cancer Institute in Rotterdam, Netherlands, provides a more comprehensive view of inflammatory remodeling during the initial phases of bone marrow diseases. Together, these two studies offer a more complete and nuanced understanding of the complex biological processes at play.
The collaborative effort involved researchers from a multitude of institutions, including UMC Mainz, the University of Basel, University Hospital Dresden, the Karolinska Institute in Sweden, The Jackson Laboratory in the USA, Sorbonne University in France, and various DKTK partner institutions, including the German Cancer Research Center (DKFZ) and NCT Dresden. The research was supported by significant funding from the DKTK-CHOICE program, an ERC grant (EpiNicheAML) awarded to Judith Zaugg, the MCSA-funded ITN ENHPATHY, EMBO, the Swiss National Foundation, and the José Carreras Leukemia Foundation. This broad international collaboration underscores the global commitment to unraveling the complexities of blood cancers and related diseases.
