Mechanisms of HOX Protein Mediated Transformation

HOX蛋白介导的转化机制

• 批准号: 7286721
• 负责人: Jay L. Hess
• 金额: $ 22.94万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7286721
• 关键词: Acute; Acute leukemia; Affect; Affinity; Animal Model; Binding; Binding Sites; Bioinformatics; Cell Line; Cells; Complex; DNA Sequence Rearrangement; Defective spinal cord development; Disease; Dysmyelopoietic Syndromes; Genes; Goals; Growth; HOX protein; HOXA9 gene; Hematopoietic; Homeobox Genes; Knowledge; Lymphoid; MEIS1 gene; Maps; Mediating; Molecular; Myeloid Leukemia; Oncogenes; Pathway interactions; Protein Isoforms; Protein Overexpression; Proteins; Regulatory Element; Risk; Role; Specificity; Work; base; cell transformation; cofactor; human MEIS1 protein; insight; knock-down; leukemia; leukemogenesis; novel therapeutics; therapeutic target; tool; tumor

DESCRIPTION (provided by applicant): Overexpression of the homeobox gene HOXA9 is emerging as an important mechanism of deregulated growth in both myelodysplasia and acute lymphoid and myeloid leukemias. HOXA9 is expressed at high levels in acute leukemias with MLL rearrangements, in myelodysplastic disorders and in high risk AMI. By itself, HOXA9 is a weak oncogene. However, in tumors, HOXA9 is almost always coexpressed with MEIS1, a HOX cofactor. Furthermore, HOXA9 and MEIS1 strongly cooperate to produce leukemia in animal models. Understanding the molecular basis for this cooperativity is pivotal for developing targeted therapy. Two general mechanisms of cooperativity are possible. One involves direct physical interaction between HOXA9 and MEIS1. This could result in altered HOXA9 localization or stability or change the affinity or specificity of HOXA9 in binding to transcriptional targets. Alternatively, HOXA9 and MEIS1 may regulate distinct pathways that cooperate in leukemogenesis. Progress toward this goal has been hampered by lack of knowledge of the proteins associated with HOXA9 and lack of insight into downstream targets of HOXA9 and MEIS1. In this proposal, two strategies would be pursued for identifying proteins associated with HOXA9 in cells transformed by HOXA9. We will determine if more than one HOXA9 complex exists in leukemia cells and what the role of the abundantly expressed HOXA9T isoform is on transformation. We will determine if MEIS1 overexpression affects the localization and composition of HOXA9 complexes and if reducing HOXA9 or MEIS1 expression blocks transformation. Cell lines with conditional forms of HOXA9 and MEIS1 or knock down will be used to identify direct and indirect targets of HOXA9. Using bioinformatics tools, we will identify and characterize regulatory elements responsive to HOXA9 in hematopoietic cells. Overall, this work will provide mechanistic insights into HOXA9 mediated transformation and is likely to uncover promising new therapeutic targets in myelodysplasia and leukemia.

描述（由申请人提供）：同源基因HOXA9的过表达是骨髓增生和急性淋巴样和髓样白血病的不受管制生长的重要机制。 HOXA9在急性白血病中以高水平的表达，并在MLL重排，骨髓发育异常和高风险AMI中表达。就其本身而言，Hoxa9是一种弱的癌基因。但是，在肿瘤中，Hoxa9几乎总是与Hox辅因子Meis1共表达。此外，Hoxa9和Meis1强烈合作在动物模型中产生白血病。了解这种合作性的分子基础对于发展有针对性的治疗至关重要。可以实现两种合作的一般机制。其中一种涉及Hoxa9和Meis1之间的直接身体互动。这可能导致HOXA9定位或稳定性改变，或改变Hoxa9与转录靶标的亲和力或特异性。另外，Hoxa9和Meis1可能调节在白血病中合作的不同途径。由于缺乏与Hoxa9相关的蛋白质知识以及对Hoxa9和Meis1下游目标缺乏洞察力的知识，朝着这一目标的进步受到了阻碍。在此提案中，将采用两种策略来识别由HOXA9转化的细胞中与HOXA9相关的蛋白质。我们将确定白血病细胞中是否存在多个Hoxa9复合物，以及大量表达的Hoxa9t同工型在转化中的作用。我们将确定MEIS1的过表达是否影响Hoxa9复合物的定位和组成以及减少Hoxa9或Meis1表达会阻塞转换。有条件形式的Hoxa9和Meis1或敲低的细胞系将用于识别HOXA9的直接和间接靶标。使用生物信息学工具，我们将识别并表征造血细胞中对HOXA9的调节元件。总体而言，这项工作将为HOXA9介导的转化提供机械见解，并可能会发现有希望的骨髓增生和白血病的新治疗靶标。