Unraveling crucial roles of homeobox gene Hlx in hematopoiesis and leukemogenesis

揭示同源框基因 Hlx 在造血和白血病发生中的关键作用

• 批准号: 8789392
• 负责人: Ashley Marie Eckel
• 金额: $ 4.24万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789392
• 关键词: Acute Myelocytic Leukemia; Address; Adopted; Biological Assay; Biology; Blood; Blood Cells; Cell Cycle Regulation; Cell Line; Cell Lineage; Cell physiology; Cells; ChIP-seq; Characteristics; Clinical; Data; Development; Disease; Disease remission; Down-Regulation; FLT3 gene; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Goals; Growth; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeobox; Homeobox Genes; Homeodomain Proteins; Human; In Vitro; Lead; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular Mechanisms of Action; Mus; Mutate; Mutation; Myelogenous; Myeloid Cells; Myeloid Leukemia; Outcome; Pathogenesis; Pathway interactions; Patients; Play; Population; Process; Regulation; Role; Signaling Protein; Stem cell transplant; Stem cells; Therapeutic Intervention; Transcriptional Regulation; Transplantation; Treatment Protocols; Up-Regulation; base; chromatin immunoprecipitation; improved; in vivo; leukemia; leukemogenesis; mouse model; novel; novel strategies; overexpression; precursor cell; progenitor; programs; research study; self-renewal; stem; stem cell biology; targeted treatment; transcription factor

DESCRIPTION (provided by applicant): While isolation of stem cells has advanced dramatically in the last few decades, understanding of the precise mechanisms that regulate the self-renewal and lineage commitment of a stem cell is still limited. During hematopoiesis, progeny of hematopoietic stem cells (HSC) become committed to differentiate into specific cell lineages to ultimately generate terminally differentiated cells. Transcription factors have been recognized for their ability to drive expression of a characteristic set of lineage-specific target genes, instructing a precursor cell to adopt a certain differentiation program. Dysregulation of transcription factor activity has an important role in leukemia, implicating these genes as potential targets for therapeutic intervention in blood, and other forms of cancer. When we analyzed purified pre-leukemic hematopoietic stem and progenitor cells (HSPC) in a murine acute myeloid leukemia (AML) model, we found 4-fold upregulation of a novel non-clustered homeobox gene, H2.0-like homeobox (Hlx), suggesting that Hlx may be involved in healthy hematopoiesis and malignant transformation. Our preliminary studies indicate that overexpression of Hlx disrupts healthy myeloid differentiation and confers unlimited serial clonogenicity and a myelomonocytic differentiation block to hematopoietic stem and progenitor cells in vitro. Furthermore, overexpression of Hlx causes loss of phenotypic HSC and persistence of an expanded, aberrant myeloid progenitor population in vivo. We also find that Hlx regulates a network of genes important for lineage commitment and myeloid differentiation of HSPC. Strikingly, we find that Hlx is overexpressed in the majority of patients with AML, and that Hlx expression is one of the strongest predictors of AML patient survival. We also find that Hlx downregulation inhibits growth of murine and human AML cells in vitro. This project aims to understand how Hlx is regulating these critical functions in HSC and during myeloid differentiation. To characterize the roles of Hlx in lineage commitment of stem and progenitor cells, as well as in myeloid differentiation and acute myeloid leukemia cells, we will utilize genetic murine models, stem cell transplantation assays and targeted reduction of Hlx levels in vivo and in vitro. To elucidate the mechanism of action of Hlx, we will study downstream pathways we have identified by transcriptional profiling and perform chromatin-immunoprecipitation to establish Hlx as a transcription factor capable of directly regulating its target genes.

描述（由申请人提供）：虽然干细胞的分离在过去的几十年里取得了巨大的进步，但对调节干细胞自我更新和谱系承诺的精确机制的理解仍然有限。在造血过程中，造血干细胞（HSC）的后代致力于分化成特定的细胞系，最终产生终末分化的细胞。转录因子因其驱动一组谱系特异性靶标的表达能力而得到认可