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

将炎症与移植物抗白血病效应联系起来：促炎蛋白 S100A 分子在早期 NK 细胞发育中的作用。

• 批准号: 496024770
• 负责人: Dr. Maya Caroline André
• 金额: --
• 依托单位: Universitätsklinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/496024770?language=en
• 关键词: Linking; inflammation; Graft; versus; Leukemia

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.

自然杀伤（NK）细胞在白血病的根除中起着重要作用。干细胞移植后，新出现的NK细胞可能在介导所谓的移植物抗白血病效应以消除最小残留白血病疾病方面发挥重要作用。在过去，我们已经在体外分化干细胞（SC）（模型1），在体内人源化NSG小鼠（模型2）和健康57 BL/6 J小鼠（模型3）中观察到低剂量5-氮杂胞苷（5-AzaC）治疗刺激NK细胞分化。目前，5-AzaC被广泛用于治疗骨髓增生异常综合征和急性髓性白血病，以逆转肿瘤抑制基因的“表观遗传沉默”并诱导癌前克隆的分化。然而，我们缺乏5-AzaC可以诱导健康SC分化的数据。我们之前大量的工作表明，5-AzaC诱导单核细胞和树突状细胞中某些促炎S100 A基因的启动子区域的选择性去甲基化，导致这些S100 A基因的转录增强。因此，我们假设（受控的）S100 A介导的炎症促进干细胞植入，从而促进NK细胞的分化。因此，我们复杂的工作计划旨在更好地了解炎症和NK细胞发育之间的机制联系，为移植后早期复发性白血病患者提供创新的治疗选择。