Researchers identify chromatin accessibility changes driving stem cell transformation in MDS

Over the past few decades, advances in hematology have illuminated how a delicate balance between stem cell self-renewal and differentiation sustains healthy blood formation. In myelodysplastic syndrome (MDS), however, this balance collapses, leading to abnormal blood cell development and a heightened risk of progression to acute myeloid leukemia. Despite major progress in genetics, the molecular events that trigger this transformation within stem cells have remained unclear.

To address this, a research team led by Professor Atsushi Iwama and Senior Assistant Professor Motohiko Oshima from the Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Japan, has uncovered how chromatin accessibility, the way DNA is packaged and exposed, changes within blood stem cells as MDS develops. The study, published in Volume 16 of the journal Nature Communications on November 28, 2025, provides a new insight into how stem cells lose their normal identity and evolve toward disease.

In healthy bone marrow, hematopoietic stem cells maintain a specific chromatin structure that preserves their renewal potential while suppressing premature activation of differentiation genes. In MDS, the researchers found that this structure is progressively altered. Using the chromatin accessibility and transcriptome analyses, they showed that MDS stem cells gradually lose the hallmarks of normal stem cells and acquire characteristics typical of myeloid progenitors.

This transformation unfolds step by step, reflecting a continuum between healthy and diseased states. "We found that chromatin accessibility in MDS stem cells is remodeled in a direction that primes them for abnormal myeloid differentiation," explains Prof. Iwama. "These findings reveal a continuum of molecular states between healthy and diseased stem cells, which may be critical to understanding how MDS evolves."

To measure this process, the team developed a "progenitor score"-a quantitative index based on chromatin accessibility profiles-that tracks how far a cell has moved toward a progenitor-like state. When applied to patient samples, the score correlated strongly with disease severity and prognosis. Patients with higher scores were more likely to experience rapid disease progression or transformation to leukemia.

"Our progenitor cell score can serve as a quantitative indicator of MDS stem cell dysregulation," says Prof. Iwama. "It could potentially help clinicians identify high-risk patients earlier and tailor their treatment accordingly."

Beyond diagnostics, the study also highlights how chromatin remodeling-the reshaping of chromatin structure-acts as a driving force in blood cancers. By comparing normal, pre-leukemic, and leukemic stem cells, the researchers found that progressive chromatin changes were a common hallmark of disease evolution. These changes were closely linked to altered transcription factor activity, particularly those governing stem cell maintenance and myeloid differentiation.

This discovery opens the door to new therapeutic possibilities. If chromatin remodeling drives the loss of stem cell identity and the shift toward a transcriptional program, then stabilizing chromatin structure or modulating transcription factor activity could potentially restore normal stem cell function. "Targeting the early epigenetic changes that precede full-blown malignancy may allow us to intervene before the disease becomes aggressive," notes Dr. Oshima.

This work represents one of the most comprehensive analyses of chromatin accessibility in MDS to date. By integrating epigenomic and transcriptomic data from a large number of patient-derived cells, the team reconstructed the molecular trajectory of MDS stem cells with unprecedented precision.

Ultimately, these results deepen the understanding of how stem cell dysregulation fuels blood disorders and highlight chromatin-based biomarkers as powerful tools for early diagnosis and risk assessment. As chromatin research advances, such approaches may lead to more precise, personalized treatments that prevent disease progression and improve outcomes for patients with MDS.