G-CSF-dependent de-/acetylation of myeloid-specific transcription factors LEF 1 and C/EBPalpha in myeloid differentiation and leukemogenesis

骨髓分化和白血病发生中骨髓特异性转录因子 LEF 1 和 C/EBPα 的 G-CSF 依赖性去/乙酰化

• 批准号: 247949958
• 负责人: Professorin Dr. Julia Skokowa, Ph.D.
• 金额: --
• 依托单位: Abteilung I: Allgemeine Pädiatrie, Hämatologie/Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/247949958?language=en
• 关键词: CSF; dependent; de; acetylation; myeloid

G-CSF is a major regulator of granulopoiesis, inducing proliferation and differentiation of hematopoietic stem cells toward granulocytes and monocytes. Failures in G-CSFR signaling are causative for two hematological disorders: severe congenital neutropenia (CN) and AML. In CN patients, myeloid progenitor cells failed to differentiate into granulocytes. In AML, hematopoietic stem cells loose the ability to differentiate and show uncontrolled proliferation. More than 90% of CN patients respond to high pharmacological doses of G-CSF (up to 80 mcg/kg/day). CN is a pre-leukemic syndrome, ca. 25% of patients develop AML. Eighty percent of CN/AML patients have acquired G-CSFR mutations, assuming the involvement of G-CSFR signaling in leukemogenesis. Post-translational modification of proteins by de-/acetylation is important for their functions, but is still poorly investigated. It is also unclear, whether G-CSFR-triggered myeloid differentiation requires de-/acetylation of myeloid-specific signaling proteins. The analysis of the de-/acetylation of transcription factors in CN, CN/AML and de novo AML patients in comparison to healthy individuals may help to delineate new signaling systems operating during myeloid differentiation or leukemogenesis. We aim: (1) to investigate the role of de-/acetylation of myeloid-specific transcription factors LEF-1 and its target C/EBPalpha in myeloid differentiation and leukemogenic transformation; (2) to analyse the role of G-CSFR/NAMPT/NAD+/SIRT system in the de-/acetylation of LEF-1 and C/EBPalpha (3) to analyse the effects of de-/acetylation of LEF-1 for its nuclear translocation by interaction with the HCLS1 protein. We hope that by modulation of de-/acetylation status of LEF-1 and C/EBPalpha proteins using pharmacological modulators of NAMPT/SIRT signalling, we will be able to regulate LEF-1/C/EBPalpha-triggered myeloid differentiation and leukemogenic transformation, which could be used for treatment of neutropenia or myeloid leukemia.

G-CSF是粒细胞生成的主要调节剂，诱导造血干细胞向粒细胞和单核细胞增殖和分化。G-CSFR信号传导的失败是两种血液疾病的原因：严重的先天性中性粒细胞减少症（CN）和AML。在CN患者中，髓系祖细胞未能分化为粒细胞。在AML中，造血干细胞失去分化能力并显示不受控制的增殖。超过90%的CN患者对高药理学剂量的G-CSF（高达80 mcg/kg/d）有反应。CN是一种白血病前期综合征。25%的患者发生AML。80%的CN/AML患者获得了G-CSFR突变，假设G-CSFR信号转导参与白血病发生。通过去乙酰化/乙酰化对蛋白质的翻译后修饰对于它们的功能是重要的，但仍然很少研究。目前还不清楚G-CSFR触发的骨髓分化是否需要骨髓特异性信号蛋白的去乙酰化/乙酰化。与健康个体相比，CN、CN/AML和新生AML患者中转录因子的去乙酰化/乙酰化分析可能有助于描绘在髓样分化或白血病发生期间操作的新信号系统。我们的目标是：（1）研究髓系特异性转录因子LEF-1及其靶基因C/EBPalpha的去乙酰化/乙酰化在髓系分化和白血病转化中的作用;（2）分析G-CSFR/NAMPT/NAD+/SIRT系统在LEF-1和C/EBPalpha去乙酰化中的作用。（3）分析LEF-1去乙酰化与HCLS 1蛋白相互作用对核转位的影响。我们希望通过使用NAMPT/SIRT信号传导的药理学调节剂调节LEF-1和C/EBPalpha蛋白的去乙酰化/乙酰化状态，我们将能够调节LEF-1/C/EBPalpha触发的髓样分化和致白血病转化，其可用于治疗中性粒细胞减少症或髓样白血病。