Contributions
Abstract: EP905
Type: E-Poster Presentation
Session title: Myelodysplastic syndromes - Biology & Translational Research
Background
Current strategies for MDS prognosis and therapy are primarily based on features of the hematopoietic system, but there is also a growing appreciation for the role that MDS-MSCs play in the development of the disease. The mechanisms by which MSCs contribute to different stages of MDS are not well understood but it is clear that there is a change in MSC biology during the course of MDS that may reflect the extent of progression or offer therapeutic opportunities for targeting the microenvironment.
To study this possibility, we retrospectively analyzed MSC samples from patients, focusing on how their characteristics change with risk classification and more importantly, with time to disease transformation. Our analysis identified gene cluster expression changes in patients that rapidly progressed to secondary leukemia and suggests targetable elements in MDS-MSCs that may help with slowing progression.
Aims
We aim to demonstrate that MDS-MSCs provide meaningful information that helps with disease prognosis and also highlight potential opportunities for targeting these MDS microenvironmental cells for therapy.
Methods
We investigated 34 MDS-BM samples with defined clinical outcomes. MSCs were derived from MDS-BM and cultured up to passage 3 for experiments. RNAseq, karyotyping, differentiation, immunophenotyping, secretome, co-culture LTC-IC assays were performed, and their results compared to discover changes related to disease progression. We also investigated the use of hypomethylating agents and MSC differentiation modulators as potential therapy for the MDS microenvironment in vitro or with pre-clinical animal models.
Results
RNAseq, secretome and functional assays show that certain unique characteristics group MDS-MSCs from patients with rapidly transforming disease better than other donor samples. These include gene and protein expression associated with changes in metabolism, hematopoietic support, angiogenesis, inflammation and ECM remodeling. Specifically, MDS-MSCs from rapidly transforming disease secreted elevated levels of macrophage inhibitory factor (MIF), pentraxin-3 (PTX3), VEGFa and reduced levels of SDF-1a. RNAseq analysis showed a cluster of >3000 genes separating samples from patients that transformed <2 years vs >5 years and implicated pathways in metabolism, ECM remodeling and angiogenesis. Finally, functional assays conducted on MDS-MSCs showed that >5 year survivors were more responsive to hypomethylating therapy and differentiation modulators as potential treatment for these stroma cells in reversing their dysplastic phenotype.
Conclusion
Analysis of MDS-MSCs may complement existing hematopoietic-based approaches for improving disease prognosis and may offer synergistic ways to slow disease progression.
Keyword(s): Mesenchymal stem cell, Myelodysplasia
Abstract: EP905
Type: E-Poster Presentation
Session title: Myelodysplastic syndromes - Biology & Translational Research
Background
Current strategies for MDS prognosis and therapy are primarily based on features of the hematopoietic system, but there is also a growing appreciation for the role that MDS-MSCs play in the development of the disease. The mechanisms by which MSCs contribute to different stages of MDS are not well understood but it is clear that there is a change in MSC biology during the course of MDS that may reflect the extent of progression or offer therapeutic opportunities for targeting the microenvironment.
To study this possibility, we retrospectively analyzed MSC samples from patients, focusing on how their characteristics change with risk classification and more importantly, with time to disease transformation. Our analysis identified gene cluster expression changes in patients that rapidly progressed to secondary leukemia and suggests targetable elements in MDS-MSCs that may help with slowing progression.
Aims
We aim to demonstrate that MDS-MSCs provide meaningful information that helps with disease prognosis and also highlight potential opportunities for targeting these MDS microenvironmental cells for therapy.
Methods
We investigated 34 MDS-BM samples with defined clinical outcomes. MSCs were derived from MDS-BM and cultured up to passage 3 for experiments. RNAseq, karyotyping, differentiation, immunophenotyping, secretome, co-culture LTC-IC assays were performed, and their results compared to discover changes related to disease progression. We also investigated the use of hypomethylating agents and MSC differentiation modulators as potential therapy for the MDS microenvironment in vitro or with pre-clinical animal models.
Results
RNAseq, secretome and functional assays show that certain unique characteristics group MDS-MSCs from patients with rapidly transforming disease better than other donor samples. These include gene and protein expression associated with changes in metabolism, hematopoietic support, angiogenesis, inflammation and ECM remodeling. Specifically, MDS-MSCs from rapidly transforming disease secreted elevated levels of macrophage inhibitory factor (MIF), pentraxin-3 (PTX3), VEGFa and reduced levels of SDF-1a. RNAseq analysis showed a cluster of >3000 genes separating samples from patients that transformed <2 years vs >5 years and implicated pathways in metabolism, ECM remodeling and angiogenesis. Finally, functional assays conducted on MDS-MSCs showed that >5 year survivors were more responsive to hypomethylating therapy and differentiation modulators as potential treatment for these stroma cells in reversing their dysplastic phenotype.
Conclusion
Analysis of MDS-MSCs may complement existing hematopoietic-based approaches for improving disease prognosis and may offer synergistic ways to slow disease progression.
Keyword(s): Mesenchymal stem cell, Myelodysplasia