Project Term: July 1, 2023 - June 30, 2025
We aim to understand the mechanism of how dysregulated Gasdermin D(GSDMD) protein propels the pathogenesis of myelodysplastic syndromes(MDS). With single-cell sequencing and patient-derived xenograft (PDX) mouse models, we want to provide pre-clinical grade data to support the concept of inhibiting GSDMD as an effective therapeutic approach in the treatment of MDS. We expect to see the great beneficial effects of GSDMD inhibition in MDS mouse models and PDX mouse models using FDA-approved drugs.
Myelodysplastic Syndromes (MDS) used to be known as pre-leukemia, the mutations in stem cells make it difficult for the bone marrow to produce blood cells, including red blood cells, white blood cells, and platelets. MDS patients may need frequent blood transfusions to stay safe. However, blood transfusion is not a sustainable solution because MDS can eventually progress to leukemia.
Only a small fraction of the bone marrow stem cells carry harmful mutations in MDS patients. But these mutant cells can prevent the normal stem cells from making functional blood cells, and these mutant cells will outgrow the normal cells and take over the bone marrow. Our previous study revealed inflammation can significantly propel the development of MDS. On one hand, inflammation can reduce the cell number of normal bone marrow stem cells. On the other hand, mutant stem cells thrive under inflammatory environments, because mutations make MDS stem cells thirsty for inflammatory cytokines for their growth and survival. Putting off the inflammation can significantly reduce the growth of MDS stem cells, and improve the production of normal blood cells from mutation-free stem cells.
A protein named Gasdermin D (GSDMD) came under our radar because GSDMD is critical for inflammatory cytokine secretion by puncturing holes in the cell membrane. However, the role of GSDMD in MDS has never been revealed. In this study, we aim to understand 1) how GSDMD contributes to the development of MDS, 2) how GSDMD helps mutant stem cells to make the bone marrow more inflammatory, and 3) to investigate the therapeutic potentials of targeting GSDMD alone or in combination with other therapies in MDS.
We created a disease mouse model that mimics human MDS, we found the deletion of the GSDMD gene in the MDS mouse model can greatly extend survival. DMF is an FDA-approved drug that was found to be able to inhibit GSDMD protein. We used DMF to treat the human MDS stem cells in test tubes, we found DMF can significantly inhibit the growth of MDS stem cells but have minimal effect on normal stem cells. This finding is extremely encouraging because it showed the important role of GSDMD in the development of MDS.
We expect to see a significant therapeutic effect from GSDMD inhibition in MDS mouse models. The success of this study will lead to great potential in clinical values, providing alternative therapeutic approaches for MDS patients who are not responsive to current treatments.