Clonal hematopoiesis and graft-versus-host disease after hematopoietic stem cell transplantation

• Applicants: Professor Dr. Frederik Damm; Professor Dr. Olaf Penack
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525808672

Graft-versus-host disease (GVHD) is the main complication of allogeneic hematopoietic stem cell transplantation (alloSCT) causing considerable mortality and morbidity. We recently found that the frequency of chronic GVHD (cGVHD) is increased in alloSCT recipients receiving stem cell grafts from donors with clonal hematopoiesis of indeterminate potential (CHIP). Another group found a connection of donor CHIP with acute GVHD. Our previous clinical work demonstrates that in particular DNMT3A mutated donor stem cells associate with an increased GVHD frequency after alloSCT. While the important role of CHIP mutations in the pathogenesis of inflammatory vascular diseases, such as atherosclerotic cardiovascular disease, has been recently elucidated, cellular and molecular mechanisms how donor CHIP and in particular DNMT3A mutations influence the development of GVHD are unclear. We demonstrated that vascular pathology is a hallmark of GVHD, which is an obvious link between clonal hematopoiesis and GVHD that we are planning to investigate. Further possible links between clonal hematopoiesis and GVHD are the implication of DNMT3A in regulation of T cell responses as well as in control of myeloid cell development and function. In the current project we are going to synergistically combine the experience of Frederik Damm’s group in clonal hematopoiesis with the expertise of Olaf Penack’s group in GVHD as well as in vascular biology. The objective of this proposal is to analyze the cellular and molecular mechanisms of DNMT3A-mediated GVHD regulation. We will use genetic modification of DNMT3A/Dnmt3a in standard murine acute and chronic GVHD models. In addition, we will transfer previously collected human leukocytes from DNMT3A-mutated vs. DNMT3A-wildtype individuals to NSG mice to study the effect of DNMT3A mutations in a humanized GVHD model. The specific aims are: Aim 1 Investigation of the effect of DNMT3A/Dnmt3a on experimental GVHD Aim 2 DNMT3A/Dnmt3a functional and mechanistic analyses during GVHD The results from the planned experiments could contribute to a better understanding of the role of donor clonal hematopoiesis during GVHD and its regulation by DNMT3A.

• DFG Programme: Research Grants