Impact of monocytes on shaping bone marrow inflammation in MDS

• Applicant: Dr. Marie Schneider
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 540018022

Myelodysplastic neoplasms (MDS) comprise a series of related bone marrow disorders, primarily of the elderly, that adversely affect both the number and integrity of maturing blood cells. Current therapy options are very limited and the tendency of MDS to progress to acute myeloid leukemia means that long-term prognosis remains very poor. Detailed molecular characterization in recent years has identified a range of common genetic lesions associated with MDS, suggesting that disease mechanisms are likely to be multifactorial. However, there is growing evidence that bone marrow inflammation is a common determinant of ineffective hematopoiesis and an important driver of disease in all cases. Based on this, it is likely that appropriate anti-inflammatory therapies will have the potential to prevent or slow disease progression. This expectation has led to the introduction of anti-inflammatory MDS therapy in clinical trial settings, although this is justified more by the urgent need for effective therapies than by a comprehensive base of preclinical data. Indeed, we still know relatively little about inflammation-related changes in the immune cell compartment and cell interactions in the bone marrow of MDS patients or how the exact patterns of inflammation may vary between individual patients. Recent work in the molecular biology and immunology of MDS has shown firstly that the underlying genetic lesion affects both inflammation pattern and disease trajectory; secondly that cells of both the innate and acquired immune system contribute to the inflammation state; and thirdly that clonal monocyte-derived cells play a central role in initiating and coordinating inflammation. Based on this previous work, it is now proposed to characterize in detail the inflammatory landscape across distinct MDS subtypes with defined mutations and thus to reveal inflammatory characteristics and immune determinants associated with each genotype. This will be achieved by applying state of the art single-cell technologies to tissue samples from MDS patients of distinct genetic subgroups in comparison to healthy individuals, placing particular focus on monocyte-derived populations. This work is expected to significantly improve the understanding of cell interactions and signaling cascades that contribute to the inflammatory environment of the bone marrow. In addition, the results will help to refine existing therapeutic approaches by enabling more efficient stratification of patients. Finally, the work has the potential to pave the way for the development of innovative therapeutic approaches based on the identification of novel targets.

• DFG Programme: Research Grants