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(申请人提供)：转录因子C/eBP�是在骨髓生成的早期阶段调节分化和增殖之间的平衡所必需的。这一功能的重要性通过观察到在许多类型的髓系白血病中C/EBP�在基因或功能上是失活的，在这些白血病中，增殖和分化之间的动态平衡协调丧失。此外，其在髓系白血病细胞系和慢性粒细胞白血病急变期患者的原代原始细胞中的异位表达可诱导粒细胞分化并抑制增殖，提示恢复功能性C/eBP�的表达或调节白血病干细胞增殖和存活所需的C/eBP�调节效应的活性可能是一种新的抗白血病治疗方法。我们发现转录抑制因子GFI-1是C/EBP�抑制增殖所必需的，它对维持造血干细胞的静止很重要。过表达GFI-1抑制bcr/abl转化细胞的增殖和集落形成，其抑制作用可通过恢复STAT 5和Mcl-1的表达而逆转，这两个转录抑制的GFI-1靶标对正常和白血病干细胞的增殖和生存至关重要。这些发现支持C/EBP�-GFI-1-STAT5/Mcl-1调节通路的存在，可用于治疗消除慢性粒细胞白血病干细胞。因此，这里提出了两种替代方法来评估干扰慢性粒细胞白血病干细胞中C/EBP�调节通路的治疗潜力：i)使用C/EBP�本身作为生物活性蛋白递送到原始慢性粒细胞白血病细胞中；ii)C/EBP�-GFI-1调节基因的遗传和药理学靶向，这些基因是慢性粒细胞白血病干细胞增殖/存活所特需的。