Role of the Hypoxia-Inducible Factor-1alpha in Myelodysplastic Syndromes

缺氧诱导因子-1α 在骨髓增生异常综合征中的作用

• 批准号: 9222755
• 负责人: Gang Huang
• 金额: $ 35.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222755
• 关键词: Acute Myelocytic Leukemia; Alleles; Blood; Blood Cells; Bone Marrow; Cell Count; Chemicals; Clonal Evolution; Complement; Complex; Data; Decitabine; Development; Dimerization; Disease; Dysmyelopoietic Syndromes; Epigenetic Process; Fibrosis; Frameshift Mutation; Gene Mutation; Gene Targeting; Genetic; Goals; HIF1A gene; Hematopoiesis; Hematopoietic stem cells; Histones; Homeostasis; Human; Hypoxia; Hypoxia Inducible Factor; Immune response; Individual; Ineffective Hematopoiesis; Inflammation; Iron; Knock-out; Lead; Lesion; Loss of Heterozygosity; Lysine; MLL gene; Maintenance; Mediating; Modeling; Molecular; Molecular Abnormality; Mus; Mutation; Newly Diagnosed; Pathogenesis; Patients; Phenotype; Pre-Clinical Model; Production; Proteins; RUNX1 gene; Repression; Role; Sampling; Secondary Myelodysplastic Syndrome; Secondary to; Series; Stem cells; Testing; Therapeutic; Therapeutic Intervention; Transcriptional Regulation; Transgenic Mice; Up-Regulation; angiogenesis; dimer; gain of function; high risk; inhibitor/antagonist; loss of function; mouse model; mutant; new therapeutic target; novel; novel therapeutics; overexpression; public health relevance; response; self-renewal; synergism; therapeutic target; transcription factor

 DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are heterogeneous disorders in which the hematopoietic stem cells (HSCs) are defective. MDS progresses to secondary acute myeloid leukemia (sAML) in about one third of patients, as additional genetic abnormalities are acquired. Epigenetic regulator MLL and transcription factor RUNX1 regulate normal hematopoiesis. We have shown that they form a complex to regulate downstream target genes. Mutations of MLL1 (in-frame partial-tandem-duplication, MLL-PTD, or MLL translocations) or RUNX1 are found in about 20-28% of MDS, particularly in high-risk MDS. sAML frequently contains both MLL-PTD and RUNX1 mutations (mRUNX1), arguing for cooperative leukemogenic synergy between these two molecular lesions. However, little is known about the molecular mechanisms underlying MDS/sAML-associated clonal evolution, ineffective hematopoiesis, and leukemic transformation. The goals of this project are to build robust and faithful mouse MDS models and to identify key targets that are critical for clonal evolution and pathogenesis of MDS/sAML. Recently, we built novel MDS mouse models by combination of MLL-PTD and Runx1 deletion or expression RUNX1 mutations in MLL-PTD background. According to our novel MDS mouse models, we identified hyperactivation of HIF-1alpha. HIF-1alpha is an essential transcription factor for hypoxic response, glycolytic energy production, HSC self-renewal, angiogenesis, systemic inflammation, immune response, fibrosis, and iron homeostasis. Thus, we hypothesize that MLL-PTD and RUNX1 mutants cooperatively activate HIF-1alpha, which contributes to the initiation, maintenance, and pathogenesis of MDS. Targeting HIF-1alpha will provide therapeutic benefit for many MDS patients. Indeed, blood specific transgenic mice expressing HIF-1alpha recapitulate the MDS phenotypes. Here we propose to determine, 1) the mechanism of HIF-1alpha up-regulation by MLL-PTD and MDS-patient-derived RUNX1 mutants; 2) the essential role of HIF-1alpha in murine and human MDS/sAML. Our study will not only provide stringent mechanistic tests of our hypotheses, but also lead to a better understanding of pathogenesis of MDS and to potential new therapeutic targets in MDS.

 描述（由申请人提供）：骨髓增生异常综合征（MDS）是造血干细胞（HSC）缺陷的异质性疾病。MDS在约三分之一的患者中进展为继发性急性髓性白血病（sAML），因为获得了额外的遗传异常。表观遗传调节因子MLL和转录因子RUNX 1调节正常造血。我们已经证明，它们形成一个复合物来调节下游靶基因。MLL 1（框内部分串联重复，MLL-PTD或MLL易位）或RUNX 1的突变在约20-28%的MDS中发现，特别是在高危MDS中。sAML通常同时含有MLL-PTD和RUNX 1突变（mRUNX 1），这表明这两种分子病变之间存在协同致白血病作用。然而，对MDS/sAML相关克隆进化、无效造血和白血病转化的分子机制知之甚少。该项目的目标是建立强大而可靠的小鼠MDS模型，并确定对MDS/sAML的克隆进化和发病机制至关重要的关键靶标。最近，我们通过结合MLL-PTD背景下的Runx 1缺失或表达RUNX 1突变建立了新的MDS小鼠模型。根据我们新的MDS小鼠模型，我们确定了HIF-1 α的过度激活。HIF-1 α是缺氧反应、糖酵解能量产生、HSC自我更新、血管生成、全身炎症、免疫反应、纤维化和铁稳态的必需转录因子。因此，我们假设MLL-PTD和RUNX 1突变体协同激活HIF-1 α，这有助于MDS的发生、维持和发病。靶向HIF-1 α将为许多MDS患者提供治疗益处。事实上，表达HIF-1 α的血液特异性转基因小鼠重现了MDS表型。在这里，我们建议确定，1）MLL-PTD和MDS患者衍生的RUNX 1突变体上调HIF-1 α的机制; 2）HIF-1 α在小鼠和人MDS/sAML中的重要作用。我们的研究不仅为我们的假说提供了严格的机制检验，而且有助于更好地了解MDS的发病机制和潜在的新的治疗靶点。