Mutual crosstalk between periodontal inflammatory conditions and blood cancer

• Applicants: Professorin Dr. Rebekka Schneider-Kramann; Professor Dr. Michael Wolf
• Subject Area: Dentistry, Oral Surgery ; Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504777725

Descriptive and association-based studies showed a link between periodontal inflammatory conditions and cancer. However, information of regulative networks on well-documented changes of alveolar and periodontal morphology in cancer initiation and progression remain unclear and haven’t been investigated using functional models. In this grant application, we will shed light on the functional association between periodontal inflammation and pre-leukemic conditions (blood cancer). Preliminary evidence from our collaborative and interdisciplinary work supports a link between mutations in hematopoietic cells (pre-leukemic condition) and alterations in the oral cavity. We sought to assess causality between mutations in hematopoietic cells and periodontal inflammation in murine pre-leukemia bone marrow transplantation models. We selected Tet2 mutations as it is the second most commonly mutated gene age-related clonal hematopoiesis and a common mutation in myeloid malignancies. TET2 mutant cells or controls were transplanted into Gli1-reporter mice. We demonstrated in previous work that Gli1+ cells are ubiquitous tissue-remodelling cells and we hypothesize that they also play a role in periodontal remodeling. Strikingly, the presence of TET2 mutations led to an increased distance between alveolar bone and enamel as measured by µCT, indicating that degrading periodontal remodeling processes are initiated through the presence of TET2 mutant cells. Additionally, we demonstrated that Gli1+ stromal cells as tissue remodeling cells and S100A8+ Gr1-CD11b+F4/80- monocytes as inflammatory cells were increased in their frequency in the periodontal tissue in the presence of (pre-leukemic) TET2 mutant cells. Based on these data we hypothesize that the inflammation caused by mutations in hematopoietic cells fuels the local inflammation in the periodontium by an increase of S100A8+ monocytes and activation of (Gli1+) stromal cells. We propose that this leads to increased local but also systemic inflammation and a vicious cycle of periodontal and systemic inflammation and potentially clonal selection of mutant (pre-leukemic) hematopoietic cells which are potentially more resistant to inflammation than wild-type cells. In aim 1, we thus plan to analyze the effect of chronic inflammation caused by periodontal inflammatory conditions on clonal selection and malignant transformation of Tet2 mutant cells. In aim 2, we will build up on our preliminary work and determine the influence of mutated hematopoietic cells on periodontal inflammatory bone degeneration.

• DFG Programme: Research Grants
• Co-Investigator: Rogerio Bastos Craveiro, Ph.D.