Nup98 Gene Rearrangements in Acute Myeloid Leukemia and Myelodysplastic Syndromes

急性髓系白血病和骨髓增生异常综合征中的 Nup98 基因重排

• 批准号: 7617138
• 负责人: NABEEL R YASEEN
• 金额: $ 10.04万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-06 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7617138
• 关键词: 4-Hydroxy-Tamoxifen; AML1-ETO fusion protein; Acute Myelocytic Leukemia; Apoptosis; Appointment; Binding; Binding Sites; Biological; Biological Assay; Bone Marrow; CD34 gene; Cell Count; Cell Cycle; Cell Line; Cells; Chimera organism; Chimeric Proteins; Chromosomal Rearrangement; Collaborations; Color; Commit; Coupled; Cycloheximide; DNA Binding; DNA Sequence; Data; Diagnostic; Doctor of Philosophy; Dominant-Negative Mutation; Dysmyelopoietic Syndromes; Electrophoretic Mobility Shift Assay; Erythrocytes; Erythroid Cells; Erythroid Hyperplasia; Estrogen Receptors; Family; Funding; Gene Expression; Gene Expression Profile; Gene Rearrangement; Gene Targeting; Genes; Genetic Transcription; Growth; HOXA9 gene; HOXA9 protein; Hematological Disease; Hematopathology; Hematopoietic; Homeobox; Human; Immunoblotting; In Vitro; Independent Scientist Award; K22 Award; Link; Luciferases; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Megakaryocytes; Methods; Molecular Profiling; Myelogenous; N-terminal; National Heart, Lung, and Blood Institute; Nuclear Extract; Nuclear Pore Complex Proteins; Oligonucleotide Microarrays; Pathology; Patients; Pattern; Physicians; Population; Principal Investigator; Proteins; Research; Research Design; Research Personnel; Rest; Role; Sampling; Scientist; Sorting - Cell Movement; Staging; Stem cells; System; Tamoxifen; Testing; Time; Universities; abstracting; career; cell transformation; chromatin immunoprecipitation; design; granulocyte; knock-down; leukemia; macrophage; mouse model; overexpression; peripheral blood; primitive cell; professor; progenitor; programs; protein protein interaction; self-renewal; single cell analysis; stem; transcription factor; vector

DESCRIPTION (provided by applicant): This is a proposal for an Independent Scientist Award (K02 - NHLBI). The studies proposed are an extension of our recently funded project R01 HL082549-01A1. The nucleoporin Nup98 gene is frequently rearranged in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), producing chimeras where the N-terminal portion of Nup98 is fused to one of 16 different proteins. The best-characterized Nup98 chimera is Nup98-HOXA9, which contains the N-terminal portion of Nup98 and the DMA-binding domain of the homeobox transcription factor HOXA9. The studies in the R01 proposal were designed to test the hypothesis that Nup98-HOXA9 is an aberrant transcription factor, identify its mechanisms of action, and elucidate the mechanisms by which it causes AML. Our most recent data indicate that Nup98-HOXA9 drastically increases the numbers of human self-renewing primitive hematopoietic cells. In contrast, its effects on the rest of human CD34+ cells are predominantly inhibitory, with increased apoptosis, reduced myeloid proliferation and differentiation, and increased numbers of erythroid cells. These findings are reminiscent of the findings in human MDS. Indeed, Nup98 chimeras, including Nup98-HOXA9 are associated with some cases of human MDS. In addition, recent studies in a mouse model show that expression of a Nup98-HOX chimera induces a severe MDS. In contrast, overexpression of HOXA9 has been linked to AML in humans and in mouse models, but not with MDS. Our hypothesis is that Nup98- HOXA9 induces MDS by inducing proliferation of primitive hematopoietic cells while inducing growth arrest and apoptosis in more mature committed progenitors. To test this hypothesis, we will determine the effects of Nup98-HOXA9 on several subsets of primary human CD34+ cells, compare them to those of HOXA9, and extend our studies of patient material to include patients with MDS. The Principal; Investigator is a physician-scientist with a tenure-track appointment as Assistant Professor of Pathology at Northwestern University. With the help of a K22 Award that ended recently, he was able to devote 75% of his time to research with the remainder spent primarily in diagnostic hematopathology. A K22 Award would enable the Principal Investigator to continue to devote at least 75% of his time to research aimed at understanding an important group of blood disorders, and establish his career as an independent investigator. (End of Abstract)

描述(由申请人提供)： 这是一个设立独立科学家奖(K02-NHLBI)的提议。建议的研究是我们最近获得资助的项目R01 HL082549-01A1的扩展。Nup98基因在急性髓系白血病(AML)和骨髓增生异常综合征(MDS)中频繁重排，产生嵌合体，其中Nup98的N端部分与16种不同蛋白质之一融合。Nup98嵌合体是Nup98-HOXA9嵌合体，它包含Nup98的N端部分和同源盒转录因子HOXA9的DMA结合域。R01方案中的研究旨在检验Nup98-HOXA9是一种异常转录因子的假设，确定其作用机制，并阐明其导致AML的机制。我们的最新数据表明，Nup98-HOXA9显著增加了人类自我更新原始造血细胞的数量。相反，它对其余的人CD34+细胞的作用主要是抑制，增加了凋亡，减少了髓系的增殖和分化，增加了红系细胞的数量。这些发现让人想起了在人类MDS中的发现。事实上，包括Nup98-HOXA9在内的Nup98嵌合体与一些人类MDS病例有关。此外，最近在小鼠模型中的研究表明，表达Nup98-Hox嵌合体会诱导严重的MDS。相反，在人类和小鼠模型中，HOXA9的过度表达与AML有关，但与MDS无关。我们的假设是，Nup98-HOXA9通过诱导原始造血细胞的增殖而诱导MDS，同时诱导更成熟的定向祖细胞的生长停滞和凋亡。为了验证这一假设，我们将确定Nup98-HOXA9对原代人类CD34+细胞的几个亚群的影响，并将它们与HOXA9进行比较，并将我们对患者材料的研究扩展到MDS患者。校长；调查员是一名内科科学家，拥有西北大学病理学助理教授的终身教职。在最近结束的K22奖的帮助下，他能够将75%的时间投入到研究中，其余的时间主要用于诊断血液病理学。K22奖将使首席调查员能够继续将至少75%的时间投入旨在了解一组重要血液疾病的研究，并确立他作为独立调查员的职业生涯。 (摘要结束)