Impact of Disease Burden and Timing of Disease Initiation on the Response to Interferonalpha (IFNa) in MPN-associated myelofibrosis

• Applicants: Professor Dr. Mathias Walter Hornef, since 8/2024; Professor Dr. Steffen Koschmieder
• Subject Area: Hematology, Oncology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417911533

Immunotherapy with pegylated interferon alpha (IFNa) is approved for the treatment of polycythemia vera (PV) patients and it can induce clinical and even molecular remission in patients with early myeloproliferative neoplasms (MPN). However, patients become unresponsive to IFNa upon disease progression. Also, it has recently become clear that the JAK2V617F mutation, which drives MPN, arises very early during childhood, suggesting a latency of several decades from emergence of the mutation until clinical manifestation of MPN disease. Thus, we hypothesize a) that proliferation of the JAK2-mutant clone is controlled by the immune system for a long time before clinical manifestation of disease, b) that there is a window of opportunity for early IFNa treatment, and c) that certain thresholds of the clonal cell burden are important for the development of bone marrow (BM) fibrosis. Therefore, in the present project, we will assess the mechanisms of IFNa responsiveness in MPN-associated myelofibrosis (MF), with a particular focus on the effects of disease burden and timing of disease initiation. During the first funding period of this CRU, we have established in vitro iPSC and primary cell mono- and co-culture systems, which now allow modeling of BM inflammation and fibrosis as well as response to IFNa and other MPN drugs. Our ongoing in vivo experiments will inform us about the overall responsiveness of BM stromal cells to IFNa treatment. In Specific Aim 1 of the current proposal, we will assess the minimal amount of MPN disease burden necessary to induce myelofibrosis, using our previously established in vitro and in vivo systems. We will use these to define the threshold of disease burden at which IFNa is able to counteract MPN-associated MF. In Specific Aim 2, we will investigate the effects of the timing of disease initiation on the development of MPN-associated myelofibrosis and the potential of IFNa to interfere with this early process. To do this, we aim to study the impact of age at disease initiation in an inducible cre-mediated JAK2V617F mouse model. Also, the age-dependent role of IFNa will be assessed. Finally, in Specific Aim 3, we will investigate the role of microbiota, regulatory T cells (Treg) and infectious disease in the age-dependent susceptibility to MF induction. The above-mentioned experiments will improve our understanding of how and when myelofibrosis develops after the acquisition of an MPN driver mutation and how factors such as age of the immune system, microbial exposure, or IFNa, may influence these processes. Ultimately, these results are expected to allow the development of strategies to treat at an early stage or even prevent MPN and/or myelofibrosis in patients using IFNa or targeting components of the immune system such as Treg.

• DFG Programme: Clinical Research Units
• Subproject of: KFO 344: Untangling and Targeting Mechanisms of Myelofibrosis in Myeloproliferative Neoplasms (MPN)
• Ehemalige Antragstellerin: Natalia Torow, Ph.D., until 8/2024