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: 7180791
• 负责人: NABEEL R YASEEN
• 金额: $ 8.37万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7180791
• 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; Nuclear Extract; Nuclear Pore Complex Proteins; Numbers; Oligonucleotide Microarrays; Pathology; Patients; Pattern; Physicians; Population; Principal Investigator; Protein Overexpression; 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; 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）： 这是独立科学家奖（K 02- NHLBI）的提案。拟议的研究是我们最近资助的项目R 01 HL 082549 - 01 A1的延伸。核孔蛋白Nup 98基因在急性髓性白血病（AML）和骨髓增生异常综合征（MDS）中经常重排，产生嵌合体，其中Nup 98的N-末端部分融合到16种不同蛋白质中的一种。Nup 98嵌合体的最佳特征是Nup 98-HOXA 9，其包含Nup 98的N-末端部分和同源框转录因子HOXA 9的DMA结合结构域。R 01提案中的研究旨在验证Nup 98-HOXA 9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。我们最近的数据表明，Nup 98-HOXA 9大大增加了人类自我更新原始造血细胞的数量。相反，其对其余人CD 34+细胞的作用主要是抑制性的，具有增加的凋亡、减少的骨髓增殖和分化以及增加的红系细胞数量。这些发现让人想起了人类MDS中的发现。事实上，Nup 98嵌合体，包括Nup 98-H 0XA 9与一些人MDS病例相关。此外，最近在小鼠模型中的研究表明，Nup 98-HOX嵌合体的表达诱导严重的MDS。相反，HOXA 9的过表达与人类和小鼠模型中的AML有关，但与MDS无关。我们的假设是Nup 98-HOXA 9通过诱导原始造血细胞的增殖同时诱导更成熟的定向祖细胞的生长停滞和凋亡来诱导MDS。为了验证这一假设，我们将确定Nup 98-HOXA 9对几种原代人CD 34+细胞亚群的影响，将它们与HOXA 9的影响进行比较，并将我们对患者材料的研究扩展到包括MDS患者。主要研究者是一名医生-科学家，在西北大学担任病理学助理教授。在最近结束的K22奖的帮助下，他能够将75%的时间用于研究，其余时间主要用于诊断血液病理学。K22奖将使主要研究者能够继续投入至少75%的时间进行旨在了解一组重要血液疾病的研究，并建立他作为独立研究者的职业生涯。 (End摘要）