Background
Myeloproliferative neoplasms (MPNs) are chronic blood cancers that are currently incurable and are driven by mutated hematopoietic stem cells (HSCs). Although patients can live with MPN for many years, the disease has the potential to progress to rapidly fatal myelofibrosis or acute leukemia.
Emerging evidence indicates that MPN-driving HSCs remodel their surrounding microenvironment. This alteration affects interactions with stromal, endothelial, and immune cells, creating a protective niche that supports malignant cell survival at the expense of healthy HSCs. Disrupting these pathogenic interactions may make MPN stem cells vulnerable to eradication.
To investigate these interactions, we conducted spatial transcriptomic profiling using the Xenium platform in our murine MPN model. These data capture cell-type-specific expression and spatial organization, providing a robust foundation for understanding MPN niche remodeling and identifying therapeutic vulnerabilities.
Aim
- Define the MPN bone marrow niche cellular composition
- Locate MPN stem cells and their cellular neighborhoods
- Identify spatially-resolved molecular interactions between MPN stem cells and niche-supporting cells.
Approach
We will explore cellular segmentation algorithms to deconvolute small and large cell types. You will integrate single-cell RNA sequencing and spatial sequencing (Xenium) data from the bone marrow of our MPN murine model using dimension-reduction methods to annotate cells and to create an MPN bone marrow atlas. We will determine the spatial proximity patterns between malignant HSCs and niche subsets using spatial statistics, such as spatial autocorrelation. We will assess how disease progression and treatment alter these spatial relationships. Additionally, we will evaluate ligand-receptor pairs that mediate malignant HSC survival and highlight potentially actionable interactions, such as cytokine signaling pathways and adhesion molecules. Finally, we will cross-reference our murine findings with human MPN datasets to prioritize interactions that are conserved in human disease for translational relevance.
Project Potential
This project has the potential to transform our understanding of the MPN stem cell niche and identify therapeutic strategies that directly target disease-driving HSCs, addressing an unmet need in current clinical practice.