At every instant, the bone marrow produces millions of new blood cells and immune cells. This continuous process of regeneration relies on a precisely tuned interplay among hematopoietic stem cells (HSCs), supportive stromal cells, and an intricate web of immune signaling pathways.
With the passage of time, this delicate equilibrium grows increasingly fragile. Factors such as advancing age, persistent inflammation, or acquired somatic mutations can interfere with the interactions between these cellular components, impairing the standard renewal of stem cells and permitting the unchecked proliferation of mutated HSCs. This mechanism underlies the development of clonal hematopoiesis of indeterminate potential (CHIP), a condition observed in roughly 10 to 20 percent of individuals aged 60 and above, rising to nearly 30 percent in those over 80 years old.
Individuals diagnosed with CHIP generally experience no overt symptoms, yet this state significantly elevates the risk of developing blood cancers by a factor of ten and doubles the chances of cardiovascular conditions as well as premature mortality. Closely related, myelodysplastic syndrome (MDS) emerges from the clonal expansion of HSCs and results in defective blood cell production along with progressive bone marrow dysfunction. This disorder impacts as many as 20 out of every 100,000 adults older than 70, with approximately 30 percent of cases progressing to acute myeloid leukemia (AML), a highly aggressive form of cancer that is frequently lethal.
Even though these conditions pose substantial health threats, the precise role played by the bone marrow microenvironment in their onset and progression has long been shrouded in uncertainty.
Charting Subtle Alterations in the Bone Marrow Niche
In an effort to elucidate how clones of mutated HSCs achieve dominance, a collaborative team of international scientists, jointly headed by Judith Zaugg from the European Molecular Biology Laboratory (EMBL) and the University of Basel, alongside Borhane Guezguez from UMC Mainz, conducted a comprehensive molecular and spatial examination of human bone marrow tissue. The study utilized samples derived from the BoHemE cohort, developed in partnership with Uwe Platzbecker at the National Center for Tumor Diseases (NCT) in Dresden.
Employing advanced techniques including single-cell RNA sequencing, imaging of biopsies, proteomics analysis, and co-culture experimental systems, the investigators generated an in-depth atlas of the bone marrow microenvironment. This mapping encompassed samples from healthy control donors, some exhibiting CHIP, as well as from patients diagnosed with MDS. Their investigations uncovered a surprising transformation in cellular composition that initiates well prior to the emergence of any clinical manifestations. Notably, the researchers identified a progressive takeover by a subset of inflammatory stromal cells, supplanting the conventional mesenchymal stromal cells (MSCs) that are essential for maintaining stem cell health and function.
‘I was taken aback by the extent of remodeling evident in the bone marrow microenvironment even among CHIP-positive individuals, though the precise causal mechanisms linking these changes remain to be fully delineated,’ remarked Zaugg, who serves as co-senior author, EMBL Group Leader, and Professor at the University of Basel.
In stark contrast to their healthy counterparts, these inflammatory mesenchymal stromal cells (iMSCs) secrete elevated levels of cytokines and chemokines stimulated by interferon. Such signaling molecules draw in and stimulate interferon-responsive T cells, which in turn amplify the inflammatory milieu. This establishes a self-perpetuating cycle that sustains ongoing inflammation, hampers physiological blood cell generation, and induces vascular modifications within the bone marrow.
Unraveling the Triggers of Bone Marrow Inflammatory Responses
Curiously, the study did not detect evidence that mutated hematopoietic cells in MDS patients directly initiate this inflammatory cascade. The team successfully distinguished mutated cells from their non-mutated counterparts through the application of SpliceUp, an innovative computational algorithm devised by co-lead author and EMBL alumnus Maksim Kholmatov, working together with Pedro Moura and Eva Hellström-Lindberg from the Karolinska Institute. SpliceUp functions by pinpointing mutated cells within single-cell datasets via the identification of aberrant RNA splicing signatures. Within MDS cases, the inflammatory dynamics dominating the microenvironment largely overshadow and displace the marrow’s typical regenerative architecture.
‘A particularly notable discovery was that MDS-derived stem cells failed to induce stromal cells to express CXCL12, a critical chemokine responsible for guiding blood cells to home into the bone marrow niche. This deficiency likely contributes to the observed breakdown in marrow functionality,’ explained Karin Prummel, co-lead author and postdoctoral researcher at EMBL.
‘It came as a genuine surprise to find no direct inflammatory influence traceable to the mutant cells themselves,’ noted Maksim Kholmatov, co-lead author and former EMBL researcher. ‘Nevertheless, when considering the alterations in T cell populations and stromal elements, these results emphatically underscore the pivotal influence of the bone marrow microenvironment on the trajectory of disease advancement.’
Chronic Inflammation as a Primary Instigator in Hematologic Disorders
Collectively, these observations position inflammation as a cornerstone in the initial stages of these pathologies, spotlighting the bone marrow microenvironment—or niche—as a prime target for therapeutic intervention. Shifting focus from solely targeting the mutated stem cells to modulating their supportive ecosystem opens avenues for proactive early interventions and preventive strategies.
Pharmacological agents with anti-inflammatory properties, or those modulating interferon pathways, could potentially safeguard bone marrow integrity in aging adults harboring CHIP. Integrating precision therapies aimed at malignant clones with microenvironment-modifying treatments might effectively halt or reverse the progression from CHIP through MDS to full-blown AML. Furthermore, the distinctive molecular signatures of iMSCs and interferon-responsive T cells hold promise as biomarkers for stratifying high-risk individuals at an early juncture.
‘Our research demonstrates that the bone marrow microenvironment profoundly influences the nascent phases of malignant transformation,’ stated Guezguez, Principal Investigator in Hematology at UMC Mainz and co-senior author. ‘With molecular profiling technologies now capable of identifying pre-leukemic conditions years ahead of symptomatic disease, insights into stromal-immune cell crosstalk lay the groundwork for interceptive therapies that avert leukemia onset.’
Inflammaging’s Broader Ramifications for Age-Associated Pathologies
Extending beyond hematologic malignancies, these insights enrich our comprehension of ‘inflammaging’—the subtle, persistent inflammatory state that underpins numerous degenerative diseases of aging, such as various cancers, cardiovascular ailments, and metabolic disturbances. Far from merely serving as a blood factory, the bone marrow emerges as both a victim and propagator of systemic inflammatory processes tied to aging. By delineating how immune and stromal cell interactions orchestrate these shifts, the study furnishes a framework for investigating analogous inflammatory restructuring in other myeloid cancers and progressed leukemias.
‘Longitudinal studies tracking these dynamics over time will be essential; our present analysis draws from cross-sectional snapshots,’ Zaugg emphasized. ‘This carries significant weight for therapeutic modalities like hematopoietic stem cell transplantation, which eradicate malignant cells while preserving the niche. We are actively probing whether the niche harbors a persistent ‘memory’ of prior disease states, potentially affecting its receptivity to infused healthy stem cells.’
This investigation coincides with a parallel study on the MDS bone marrow niche, also featured in Nature Communications and spearheaded by Marc Raaijmakers from Erasmus MC Cancer Institute in Rotterdam. Synergistically, these works provide a holistic perspective on inflammatory niche remodeling during the incipient stages of bone marrow pathologies.
