Triad1 regulates myelopoiesis and functions as a leukemia suppressor

Triad1 调节骨髓细胞生成并发挥白血病抑制因子的作用

• 批准号: 8891685
• 负责人: Elizabeth Ann Eklund
• 金额: $ 35.34万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891685
• 关键词: 11q23; Acute Myelocytic Leukemia; Affinity; Apoptosis; Bone Marrow; CREBBP gene; Cell Proliferation; Cell Survival; Cells; Chimeric Proteins; Cytokine Receptors; Development; Disease Progression; Drug resistance; EGF gene; Epithelial Cells; Event; FLT3 gene; Feedback; Gene Targeting; Genes; Genetic Transcription; Goals; Granulopoiesis; Growth Factor; Homeobox Genes; Human; Hypersensitivity; In Vitro; Incidence; Individual; Inositol; Integrins; Lesion; Mediating; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Myelopoiesis; Myeloproliferative disease; Phosphorylation; Phosphotransferases; Production; Proteins; Recycling; Refractory; Repression; Role; Sampling; Signal Transduction; Stem cells; Stream; Time; Transplantation; Tyrosine Phosphorylation; Ubiquitin; Ubiquitination; autocrine; cytokine; homeodomain; human SYK protein; in vivo; leukemia; leukemogenesis; mutant; novel; outcome forecast; overexpression; prevent; progenitor; promoter; public health relevance; receptor; response; therapeutic target; transcription factor; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Triad1 is an E3 ubiquitin ligase that impairs proliferation of bone marrow progenitor cells and increases in expression during granulopoiesis. We found that Triad1 enhances ubiquitin (Ub) mediated degradation of Fgf- R1, Flt3 and av integrin in myeloid cells. Fgf-R1 and Flt3 activate phospho-inositol-3-kinase; resulting in stabilization of ßcatenin and expression of ßcatenin-target-genes involved in proliferation/survival. Syk is activated by avß3 integrin, resulting in Pak1-dependent proliferatin and PLC-dependent survival. Triad1 also inhibits Ub of p53 by Mdm2. We hypothesize that increasing Triad1 expression during granulopoiesis favors degradation of Fgf-R1, Flt3 and avß3 integrin, but stabilizes p53; decreasing proliferation and enhancing sensitivity to apoptosis. This identifies a possible leukemia suppressor function for Triad1, since impaired activity would sustain Fgf-R1, Flt3 and avß3 signaling and destabilize p53. Consistent with this, Triad1 is specifically decreased in subsets of acute myeloid leukemia (AML) with MLL-translocations (i.e. 11q23-AML) or activating FLT3 mutation. Our studies identified a mechanism for this. 11q23-AML is characterized by increased expression of a set of HOX genes, including HoxA9 and A10. We found that HoxA9 and A10 regulate transcription of ARIH2 (encoding Triad1) in a manner that requires cytokine-induced tyrosine phosphorylation of the Hox proteins. We found that constitutive activation of Shp2-PTP blocks ARIH2 transcription by preventing Hox phosphorylation. Interestingly, FLT3 mutations are frequent in Hox-over- expressing AML and activate Shp2. A myeloproliferative neoplasm (MPN) develops in mice transplanted with bone marrow expressing MLL1 fusion proteins or overexpressing HoxA9 or A10. This MPN evolves to AML over time, suggesting that Hox-overexpression is inadequate for AML in the absence of cooperating mutations. We find constitutive Shp2-activation performs this function. We hypothesize Triad1 is a leukemia suppressor that decreases proliferation/survival of cytokine-stimulated progenitor cells, and that impaired Triad1-activity facilitates disease progression/drug resistance in Hox-overexpressing AML. We will pursue this via 3 aims: Aim 1: Identify Triad1-regulated events that have functional implications for leukemia. The influence of Triad1 on Ub/degradation of Fgf-R1, avß3, Flt3 and p53 will be investigated in vitro and in vivo. Aim 2: Determine if Triad1 is a leukemia suppressor in AML with Hox-overexpression and Shp2 activation. The contributions of Triad1-expression and Shp2-activation to drug resistance/disease progression will be explored in studies with murine AML models and human AML bone marrow samples. Aim 3: Define targetable mechanisms of leukemia suppression by Triad1. Contributions of Fgf-R1, Flt3, av integrin and p53 to leukemogenesis and drug resistance will be explored in vivo in murine models. Hox-overexpressing AML has poor prognosis and is treatment refractory. Clarifying cooperating lesions and down-stream events may suggest therapeutic targets for this subset of individuals.