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

 描述(申请人提供)：骨髓增生异常综合征(MDS)是一种造血干细胞(HSCs)缺陷的异质性疾病。在大约三分之一的患者中，MDS进展为继发性急性髓系白血病(SAML)，因为获得了更多的遗传异常。表观遗传调节因子MLL和转录因子RUNX1调节正常的造血。我们已经证明它们形成了一个复合体来调节下游的靶基因。MLL1(框内部分串联复制，MLL-PTD或MLL易位)或RUNX1突变在大约20%-28%的MDS中被发现，特别是在高危MDS中。SAML经常同时包含MLL-PTD和RUNX1突变(MRUNX1)，认为这两种分子病变之间存在协同致白血病作用。然而，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健壮和可靠的小鼠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点。最近，我们通过MLL-PTD和RUNX1缺失或表达RUNX1突变相结合的方法建立了新的MDS小鼠模型。根据我们的新的MDS小鼠模型，我们发现了HIF-1α的过度激活。HIF-1α是低氧反应、糖酵解能量产生、HSC自我更新、血管生成、全身炎症、免疫反应、纤维化和铁稳态所必需的转录因子。因此，我们假设MLL-PTD和RUNX1突变体协同激活HIF-1α，这有助于MDS的启动、维持和发病。靶向HIF-1α将为许多MDS患者提供治疗益处。事实上，表达HIF-1α的血液特异性转基因小鼠概括了MDS的表型。在这里，我们建议确定：1)MLL-PTD和MDS患者来源的RUNX1突变体上调HIF-1α的机制；2)HIF-1α在小鼠和人MDS/SAML中的重要作用。我们的研究不仅将为我们的假说提供严格的机制测试，而且将有助于更好地理解MDS的发病机制，并为MDS寻找潜在的新的治疗靶点。

 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.