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Role of PHF6 in Normal Hematopoiesis and hematopoietic stem cell biology

PHF6 在正常造血和造血干细胞生物学中的作用

基本信息

批准号：
10198036
负责人：
Feng-Chun Yang
金额：
$ 30.97万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198036
关键词：
AML/MDS Acetylation Acute Myelocytic Leukemia Acute T Cell Leukemia Address Affect Affinity Chromatography Amino Acids Binding Biological Biological Assay Biotinylation Body Weight decreased Borjeson-Forssman-Lehmann syndrome Cell physiology Cells Cellular biology ChIP-seq Chromatin Chromatin Remodeling Factor Chronic Myelomonocytic Leukemia Clinical Research Coupled Data Development Disease Dysmyelopoietic Syndromes Enzymes Exhibits Fingers Frameshift Mutation Gene Expression Gene Family Genes Genetic Genetic Transcription Genomics Germ-Line Mutation Goals Hand Hematologic Neoplasms Hematology Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Histones Human Hypogonadism In Situ In Vitro Knock-out Knowledge Lesion Link Maps Mediating Mental Retardation Modeling Molecular Mus Mutate Mutation Myeloproliferative disease Nonsense Mutation NuRD complex Nuclear Obesity PHD Finger Patients Pharmaceutical Preparations Phenotype Plants Play Proteins Regulation Role Structure Testing Time Transcription Elongation Transcriptional Regulation Transgenic Mice Transplantation Tumor Suppressor Proteins Vertebrates X Chromosome Xq26 Zinc Fingers analog cell behavior clinically significant gain of function genome-wide hematopoietic stem cell self-renewal histone modification homeodomain improved in vivo loss of function male member mouse model mutant new therapeutic target overexpression protein protein interaction self-renewal stem cell biology stem cell function transcriptome sequencing

项目摘要

The plant homeodomain finger 6 (PHF6) is a member of the plant homeodomain (PHD)-like finger family genes. PHF6 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL, ~15%) and various myeloid malignancies including acute myeloid leukemia (AML, ~3%), myelodysplastic syndrome (MDS, ~3%) and chronic myelomonocytic leukemia (CMML, ~5%). Interestingly, the PHF6 genetic lesions in hematological malignancies are largely frameshift and nonsense mutations distributed throughout the gene, indicating that these PHF6 mutations likely result in the loss of WT PHF6 and the expression of a truncated PHF6. Furthermore, clinical studies showed that PHF6 mutations confer worse overall survival in patients with MDS and AML. Despite the clinical significance of PHF6 mutations in hematologic neoplasms, the role of PHF6 in normal hematopoiesis and the impact of its mutations on the hematopoietic stem/progenitor cell (HSPC) functions remain unknown. In addition, it is not known whether the truncated-PHF6 leads to a bona fide loss-of- function or exerts a gain-of-function in hematopoiesis. Given the fact that PHF6 is located on the X chromosome and its mutations are male dominant, we hypothesize that the PHF6 mutations confer a gain-of- function in vivo. We therefore generated a conditional Phf6 knock-out (Phf6flox) mouse model to determine the role of PHF6 in normal hematopoiesis and whether loss of Phf6 affect HSPC cell fate and functions. In addition, we also established two transgenic mice expressing two different patient-derived truncated PHF6 (Phf6R274X and Phf6R342XTg) solely in hematopoiesis to determine the impact of truncated PHF6 on HSPC activities. Our preliminary data showed that Phf6-loss in mice increase hematopoietic stem cell self-renewal, indicating that PHF6 plays an important role in HSC regulation. We also found that PHF6 truncation expression confer a gain-of-function to promote HSC self-renewal. With these models in hand, we will determine the hematological phenotypes of mice with combined Phf6-inactivation and expression of truncated PHF6 in hematopoiesis, and define the cellular and molecular mechanisms by which PHF6 and its truncated mutations impact on HSPC functions. Mechanistically, we will identify key PHF6 and truncated PHF6 binding partners and determine the importance of these interactions to their genomic localization and common target gene expression in HSPCs. These studies will greatly improve our understanding for the role of PHF6 in normal hematopoiesis as well as the impact of PHF6 mutations on HSPC functions. Moreover, these PHF6 mutant models offer a biological platform in which drugs can be tested and developed. These studies are timely and fundamentally important for advancing our knowledge on PHF6 in normal hematopoiesis and HSPC biology.

植物同源结构域指6（PHF 6）是植物同源结构域（PHD）样指家族基因的一员。 PHF 6在T细胞急性淋巴细胞白血病（T-ALL，~15%）和各种髓系白血病中经常发生突变。恶性肿瘤包括急性髓性白血病（AML，~3%）、骨髓增生异常综合征（MDS，~3%）和慢性粒单核细胞白血病（CMML，约5%）。有趣的是，PHF 6基因在血液系统中的损害，恶性肿瘤主要是移码突变和分布在整个基因中的无义突变，表明这些PHF 6突变可能导致WT PHF 6的丢失和截短的PHF 6的表达。此外，临床研究表明，PHF 6突变导致MDS患者的总体生存率更差和AML。尽管PHF 6突变在血液肿瘤中具有临床意义，但PHF 6在血液肿瘤中的作用仍有待进一步研究。正常造血及其突变对造血干/祖细胞（HSPC）的影响功能仍然未知。此外，尚不清楚截短的PHF 6是否会导致真正的在造血中发挥功能或发挥功能增益。考虑到PHF 6位于X 染色体及其突变是男性显性的，我们假设PHF 6突变赋予了一个获得性的，在体内发挥作用。因此，我们产生了条件性Phf 6敲除（Phf 6 flox）小鼠模型，以确定 PHF 6在正常造血中的作用以及Phf 6的缺失是否影响HSPC细胞命运和功能。在此外，我们还建立了两个转基因小鼠表达两种不同的患者源性截短PHF 6 （Phf 6 R274 X和Phf 6 R342 XTg），以确定截短的PHF 6对HSPC的影响活动我们的初步数据显示，小鼠中Phf 6的缺失增加了造血干细胞的自我更新，表明PHF 6在HSC调节中起重要作用。我们还发现PHF 6截短表达赋予功能获得以促进HSC自我更新。有了这些模型，我们将确定联合Phf 6失活和截短的PHF 6表达的小鼠的血液学表型，造血，并定义PHF 6及其截短突变的细胞和分子机制，影响HSPC功能。从机制上讲，我们将确定关键的PHF 6和截短的PHF 6结合伙伴并确定这些相互作用对它们的基因组定位和共同靶基因的重要性在HSPCs中表达。这些研究将极大地提高我们对PHF 6在正常肝细胞中作用的认识。造血以及PHF 6突变对HSPC功能的影响。此外，这些PHF 6突变体模型提供了一个生物平台，可以在其中测试和开发药物。这些研究是及时的，这对于我们进一步了解PHF 6在正常造血和HSPC生物学中的作用至关重要。