Profile:
Simón Méndez-Ferrer, PhD
Rutgers University
Beyond mutant cells: Dr. Simón Méndez-Ferrer on the role of the bone marrow environment in myelofibrosis (MF).
In a healthy body, the bone marrow is a bustling ecosystem, teeming with diverse cellular species, each playing a supportive role and maintaining balance. Stem cells stand at the heart of this environment, sustaining blood production through the process of hematopoiesis. Supportive elements — structural tissue, nerve fibers, and blood vessels — shape the environment where red, white, and platelet cells mature. But in myelofibrosis (MF), a rare and severe form of bone cancer, this once-thriving environment becomes scarred and unproductive.
The damage doesn’t happen overnight. Simón Méndez-Ferrer PhD, a researcher at the University of Cambridge and 2024 MPN Challenge™ award recipient, studies how the bone marrow microenvironment (BME) impacts blood cancer. Dr. Méndez-Ferrer explains that “there has to be critical threshold damage of the microenvironment to really lead into disease manifestation.” Like a forest suffering from prolonged drought and pollution, the bone marrow can gradually lose its ability to function. Once-resilient support structures weaken, and a cascade of destructive changes ensues.
A microenvironment in decline
Like foliage and fauna taking root and nesting among creeks, hills, or sunny spots, the cells in the bone marrow take residence in various nooks and compartments. Hematopoietic stem cells are typically thought to nestle along the inner surface of the bone. But recent findings suggest they may roam more freely, dispersing throughout the marrow or clustering near nutrient rich fat cells.
In MF, the delicate balance of the bone marrow ecosystem is collapsing due to the expansion of fibrotic tissue leaving little room for healthy growth. “The hematopoietic tissue cannot really produce blood normally because it becomes like scar tissue,” Dr. Méndez-Ferrer describes how fibrosis replaces healthy niches. This can lead to life-threatening complications — severe anemia, an overactive immune system, and the risk of progression to acute leukemia.
The once-flourishing forest becomes littered with dry patches of cracked earth and the marrow can no longer support life as it once did.
The result of environmental stress
Mutant stem cells, often carrying genetic changes like JAK2 mutations, take advantage of environmental instability and expand unchecked.
“We’re looking at a continuous process,” Dr. Méndez-Ferrer explains how a stem cell with a particular mutation can replicate into many identical clones. Like invasive species, these clones can outcompete their counterparts. Whether they have unique survival advantages or simply tolerate the damaged environment, mutated cells thrive in these harsh conditions.
“The progressive damage of the microenvironment allows this mutant clone to give rise to clonal hematopoiesis that can now be detected in peripheral blood.” In other words, the disruption to the ecosystem doesn’t just support the disease — it actively helps it spread.
Rogue species and [cyto]toxic conditions
A major driver of this transformation is chronic inflammation. Inflammatory signals are useful messages of the immune system, except when present in excess. Chronic inflammation saturates the bone marrow with harmful levels of these signals, much like pollution contaminating once-fertile land.
Commenting on the expansion of clonal mutant cells, Dr. Méndez-Ferrer explains that “part of this capacity to grow is because of this inflammatory damage caused by this cytokine.” One of the key players is interleukin-1 beta (IL-1β), a pro-inflammatory molecule that disrupts essential supportive cells. His research suggests that IL-1B’s influence is especially felt in the beginning of the progression towards MF. “Nerve cells, or the supportive glial cells for the nerve cells, are very sensitive to this IL-1β. This damage unleashes the capacity of the mutant clone to expand.”
In any ecosystem, there are keystone species that, if removed, propel the entire environment towards collapse. “One of the key neighbors for the blood stem cell is actually the other stem cell that you can find inside the bones, which is the mesenchymal stem cell,” Dr. Méndez-Ferrer explains. Mesenchymal stem cells normally regulate hematopoietic stem cell function and support a healthy BME. However, they can lose their ability to maintain order in myelofibrotic bone marrow, allowing disease progression.
Landscape influences disease progression
Not all affected individuals experience MF in the same way. Just as ecosystems vary in resilience, some BMEs seem to resist damage longer than others. “We found that there are different types of microenvironments where these mutant cells can reside,” Dr. Méndez-Ferrer says. “Some of them are more permissive, some are more restrictive in terms of limiting the capacity of the mutant stem cells to grow. Depending on this, you could have a more aggressive or a more benign type of disease.”
This variability could explain why some patients progress rapidly while others remain stable for years or why there are differences in treatment response. The more we learn about an environment the better able we are to answer a crucial question: Can we repair it before it’s too late?
Restoration efforts
Scientific understanding evolves, and with it, so does our approach to disease. Understanding MF as an ecosystem in crisis offers a powerful new perspective on the disease — one that highlights the delicate balance that exists within us and the urgent need to protect it.
If the ecosystem of the bone marrow is too damaged, no treatment aimed solely at the malignant cells will be enough. While JAK inhibitors manage symptoms, emerging research suggests that restoring the BME itself is just as critical.
Dr. Méndez-Ferrer’s team is working to restore healthy relationships in the BME. “We found ways to sort of prevent this development, just interfering with these cell-cell communications in the environment where the mutant clone resides,” he explains.
Potential strategies include:
- blocking inflammatory signals to reduce damage to supportive cells
- strengthening mesenchymal stem cells and nerve fibers to rebuild niches
- preventing fibrosis formation to keep the bone marrow functional for as long as possible
The bone marrow in MF is not beyond saving. By repairing the environment itself, scientists may open new paths toward disease-modifying treatments. In doing so, we move closer to a world where MF is not just managed but microenvironments are fundamentally restored.
Sources:
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