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

疾病负担和疾病发生时间对 MPN 相关骨髓纤维化中干扰素α (IFNa) 反应的影响

• 批准号: 428858786
• 负责人: Professor Dr. Steffen Koschmieder
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/428858786?language=en
• 关键词: Impact; Disease; Burden; Timing; Initiation

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.

聚乙二醇化干扰素α（IFNa）免疫疗法被批准用于治疗真性红细胞增多症（PV）患者，它可以诱导早期骨髓增生性肿瘤（MPN）患者的临床甚至分子缓解。然而，随着疾病进展，患者对 IFNa 失去反应。此外，最近已经明确，驱动 MPN 的 JAK2V617F 突变在儿童时期很早就出现，这表明从突变出现到 MPN 疾病的临床表现有数十年的潜伏期。因此，我们假设：a) 在出现疾病临床表现之前，JAK2 突变克隆的增殖在很长一段时间内受到免疫系统的控制，b) 存在早期 IFNa 治疗的机会窗口，c) 克隆细胞负荷的某些阈值对于骨髓 (BM) 纤维化的发展很重要。因此，在本项目中，我们将评估 MPN 相关骨髓纤维化 (MF) 中 IFNa 反应性的机制，特别关注疾病负担和疾病发生时间的影响。在该 CRU 的第一个资助期间，我们建立了体外 iPSC 和原代细胞单培养和共培养系统，现在可以对 BM 炎症和纤维化以及对 IFNa 和其他 MPN 药物的反应进行建模。我们正在进行的体内实验将告诉我们 BM 基质细胞对 IFNa 治疗的总体反应性。在当前提案的具体目标 1 中，我们将使用我们之前建立的体外和体内系统来评估诱发骨髓纤维化所需的最小 MPN 疾病负担。我们将使用这些来定义 IFNa 能够抵消 MPN 相关 MF 的疾病负担阈值。在具体目标 2 中，我们将研究疾病发生时间对 MPN 相关骨髓纤维化发展的影响以及 IFNa 干扰这一早期过程的潜力。为此，我们的目标是在可诱导的 cre 介导的 JAK2V617F 小鼠模型中研究年龄对疾病起始的影响。此外，还将评估 IFNa 的年龄依赖性作用。最后，在具体目标 3 中，我们将研究微生物群、调节性 T 细胞 (Treg) 和传染病在 MF 诱导的年龄依赖性易感性中的作用。上述实验将提高我们对获得 MPN 驱动突变后骨髓纤维化如何以及何时发生以及免疫系统年龄、微生物暴露或 IFNa 等因素如何影响这些过程的理解。最终，这些结果预计将有助于制定策略，在使用 IFNa 或靶向免疫系统成分（如 Treg）的患者中进行早期治疗，甚至预防 MPN 和/或骨髓纤维化。