Targeting the C/EBPalpha-Gfi-pathway in CML stem cells

靶向 CML 干细胞中的 C/EBPalpha-Gfi 通路

• 批准号: 9120811
• 负责人: BRUNO CALABRETTA
• 金额: $ 32.16万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120811
• 关键词: Biological Response Modifier Therapy; Blast Cell; Blast Phase; CCAAT-Enhancer-Binding Protein-alpha; CCAAT-Enhancer-Binding Proteins; CD34 gene; Cells; Chimeric Proteins; Chronic Myeloid Leukemia; Ectopic Expression; Equilibrium; Genes; Genetic; Health; Hematopoietic stem cells; In Vitro; Mus; Myeloid Leukemia; Myelopoiesis; Pathway interactions; Patients; Proteins; RNA Interference; Regulation; Regulatory Pathway; Staging; Stat5 protein; Stem cells; Therapeutic; Therapeutic Effect; Transcription Repressor/Corepressor; bcr-abl Fusion Proteins; cell transformation; leukemia; leukemic stem cell; novel; overexpression; transcription factor

DESCRIPTION (provided by applicant): The transcription factor C/EBP� is required for regulation of the balance between differentiation and proliferation during the early stages of myelopoiesis. The importance of this function is demonstrated by the observation that C/EBP� is genetically or functionally inactivated in many types of myeloid leukemia in which the homeostatic coordination between proliferation and differentiation is lost. Moreover, its ectopic expression in myeloid leukemia lines and in primary blast cells from chronic myelogenous leukemia (CML)-blast crisis patients induces granulocytic differentiation and inhibits proliferation; this suggests that restoring the expression of functional C/EBP� or modulating the activity of C/EBP�-regulated effectors required for proliferation and survival of leukemic stem cells may be a novel anti-leukemia therapy. We found that the transcription repressor Gfi-1, which is important for maintaining the quiescence of hematopoietic stem cells, is required for the proliferation inhibitory effects of C/EBP�. Overexpression of Gfi-1 suppresses proliferation and colony formation of BCR/ABL-transformed cells and its inhibitory effects are reversed by restoring the expression of STAT 5 and Mcl-1, two transcriptionally repressed Gfi-1 targets important for proliferation and survival of normal and leukemic stem cells. These findings support the existence of a C/EBP�-Gfi-1-STAT5/Mcl-1 regulatory pathway that could be exploited therapeutically for the elimination of CML stem cells. Thus, two alternative approaches are proposed here to assess the therapeutic potential of perturbing C/EBP�-regulated pathways in CML stem cells: i) the use of C/EBP� itself delivered as a biologically active protein to primitive CML cells; ii) the genetic and pharmacological targeting of C/EBP� -Gfi-1-regulated genes specifically required for the proliferation/survival of CML stem cells.

描述（由应用程序提供）：在骨髓虫早期阶段的分化与增殖之间的平衡需要调节转录因子C/EBP。观察到C/EBP在许多类型的髓样白血病中被遗传或功能失活的观察结果证明了这一功能的重要性，其中丢失了增殖和分化之间的稳态协调。此外，它在髓样白血病系和来自慢性粒细胞性白血病（CML） - 抑制性危机患者的异位表达诱导粒细胞分化并抑制增殖；这表明，恢复功能性C/EBP的表达或调节白血病干细胞增殖和存活所需的C/EBP调节作用的活性可能是一种新型的抗白血病治疗。我们发现，C/EBP的增殖抑制作用需要转录复制GFI-1，这对于维持造血干细胞的静止很重要。 GFI-1的过表达抑制了BCR/ABL转化细胞的增殖和菌落形成及其抑制作用，通过恢复STAT 5和MCL-1的表达来逆转，两个转录代表的GFI-1代表的GFI-1靶标对于正常和白血病干细胞的增殖和存活至关重要。这些发现支持C/EBP-GFI-1-STAT5/MCL-1调节途径，可以热探索以消除CML干细胞。这里提出了两种替代方法，以评估CML干细胞中C/EBP调节途径扰动的治疗潜力：i）使用作为生物活性蛋白递送的C/EBP自身使用对原始CML细胞的使用； ii）C/EBP-GFI-1调节的基因的遗传和药物靶向是CML干细胞的增殖/存活所需的。