To dissect the role of the alarmins S100A8/S100A9 in bone marrow fibrosis and clonal evolution in myeloproliferative neoplasms

剖析警报素 S100A8/S100A9 在骨髓增生性肿瘤的骨髓纤维化和克隆进化中的作用

• 批准号: 394854308
• 负责人: Dr. Nils Leimkühler
• 金额: --
• 依托单位: Klinik für Hämatologie und Stammzelltransplantation
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/394854308?language=en
• 关键词: dissect; role; alarmins; S100A8; S100A9

Primary myelofibrosis (PMF) is the most aggressive subtype of myeloproliferative neoplasms (MPNs) and the prototypic example of bone marrow (BM) fibrosis. In this condition, the hematopoietic marrow is incrementally replaced by scar tissue ultimately resulting in bone marrow failure. To this date, allogenic stem cell transplantation is considered the only therapeutic op-tion with curative intentions, which itself is associated with high rates of mortality and morbidity.There is increasing evidence that an altered microenvironment and inflammatory processes play an important role in the progression of the disease to a life-threatening condition, including leukemic transformation. The specific mechanisms that cause fibrosis and selection of the malignant MPN hematopoietic stem cells (HSCs) over normal HSCs are only incompletely understood, especially since the fibrosis-driving cells have remained obscure. The lack of a deeper pathophysiological understanding of disease progression limits pharmacological targeted therapy. Recent findings in the Schneider lab demonstrate that Gli1+ cells are key drivers of BM fibrosis and that they represent an attractive therapeutic target. This puts me in the unique position to dissect mechanisms in the PMF pathogenesis and to discover novel therapeutic possibilities for this fatal disease. Based on preliminary work in the Schneider and Raaijmakers lab, I propose that the alarmins S100A8/S100A9 contribute to initiation of BM fibrosis and during progression to niche-induced genotoxic stress driving the loss of normal HSC function, and selection of the MPN clone over normal hematopoieisis. Targeting S100A8/S100A9 and downstream targets mediating these early events could attenuate BM fibrosis and prevent disease progression and leukemogenesis.I will apply state-of-the-art techniques (genetic-fate-tracing, conditional genetic knockout-mice, CRISPR/Cas9 gene editing) and will validate our findings in patient samples with the ultimate goal to optimize the diagnosis of pre-fibrotic states of PMF and to develop novel therapeutic strategies with curative intentions.

原发性骨髓纤维化（PMF）是骨髓增生性肿瘤（MPN）中最具侵袭性的亚型，也是骨髓（BM）纤维化的典型例子。在这种情况下，造血骨髓逐渐被瘢痕组织取代，最终导致骨髓衰竭。到目前为止，同种异体干细胞移植被认为是唯一具有治愈目的的治疗选择，其本身与高死亡率和发病率相关，越来越多的证据表明，改变的微环境和炎症过程在疾病进展为危及生命的疾病（包括白血病转化）中起重要作用。导致纤维化和恶性MPN造血干细胞（HSC）相对于正常HSC的选择的特定机制仅不完全理解，特别是因为纤维化驱动细胞仍然不清楚。对疾病进展缺乏更深层次的病理生理学理解限制了药物靶向治疗。Schneider实验室的最新发现表明，Gli 1+细胞是BM纤维化的关键驱动因素，它们代表了一个有吸引力的治疗靶点。这使我处于独特的位置，剖析PMF发病机制，并发现这种致命疾病的新治疗可能性。基于Schneider和Raaijmakers实验室的初步工作，我提出alarmins S100 A8/S100 A9有助于BM纤维化的启动，并在进展到小生境诱导的遗传毒性应激期间驱动正常HSC功能的丧失，以及选择MPN克隆而不是正常造血。靶向S100 A8/S100 A9和介导这些早期事件的下游靶点可以减轻BM纤维化并防止疾病进展和白血病发生。（遗传命运追踪，条件遗传敲除小鼠，CRISPR/Cas9基因编辑），并将验证我们在患者样本中的发现，最终目标是优化前PMF的纤维化状态，并开发具有治愈意图的新的治疗策略。

项目成果

Dissecting the Functional Reprogramming of the Microenvironment in Bone Marrow Fibrosis at the Single Cell Level

在单细胞水平上剖析骨髓纤维化微环境的功能重编程

• DOI: 10.2139/ssrn.3493957
• 发表时间: 2019
• 期刊: SSRN Electronic Journal
• 作者: Leimkühler;Nils B;Ronghui;Gleitz;Hélène F.E;Snoeren;Inge A. M;Stijn N.R;Christoph;Stalmann;Ursula S. A;Buesche;Guntram;Kreipe;Gütgemann;Philippe
• 通讯作者: Philippe