Linking inflammation to Graft-versus-Leukemia Effects: Role of pro-inflammatory protein S100A molecules in early NK cell development.

• Applicant: Dr. Maya Caroline André
• Subject Area: Hematology, Oncology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496024770

Natural killer (NK) cells play an important role in the eradication of leukemia. Following stem cell transplantation, emerging NK cells may execute an important role in mediating so-called graft-versus-leukemia effects to eliminate minimal residual leukemic disease. In the past, we have observed in vitro in differentiating stem cells (SCs) (model 1), in vivo in humanized NSG mice (model 2) and in healthy 57BL/6J mice (model 3) that a low-dose therapy with 5-Azacytidine (5-AzaC) stimulates NK cell differentiation. Currently, 5-AzaC is widely used in the treatment of myelodysplastic syndromes and acute myeloid leukemia to reverse the “epigenetic silencing” of tumor suppression genes and to induce differentiation of pre-malignant clones. However, we lack data that 5-AzaC may induce the differentiation of healthy SCs. Our substantial previous work demonstrates that 5-AzaC induces selective de-methylation in the promotor region of certain pro-inflammatory S100A genes in monocytes and dendritic cells resulting in enhanced transcription of those S100A genes. We therefore hypothesize that a (controlled) S100A-mediated inflammation promotes stem cell engraftment and as such the differentiation of NK cells. Our complex working program is therefore designed to achieve a better understanding of the mechanistic link between inflammation and NK cell development to offer patients with relapsing leukemia early post transplantation an innovative therapeutic treatment option.

• DFG Programme: Research Grants