Role of Shp2 in FLT3-ITD-Induced Leukemogenesis

Shp2 在 FLT3-ITD 诱导的白血病发生中的作用

基本信息

批准号：
8444574
负责人：
REBECCA J. CHAN
金额：
$ 30.04万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444574
关键词：
Acute Myelocytic Leukemia Acute leukemia Adult Adult Acute Myeloblastic Leukemia Age-Years Amino Acids BAY 54-9085 Binding Bone Marrow Cells Clinical Trials Data Development Disease Drops Elderly FLT3 gene Family Genes Genetic Growth Guanosine Triphosphate Phosphohydrolases Hematopoietic High Dose Chemotherapy Human In Vitro Incidence Individual Investigation Ligands Molecular Mononuclear Mutate Mutation Myelogenous Myeloid Leukemia Myeloproliferative disease Nuclear PTPN11 gene Pathogenesis Patients Phenylalanine Population Process Protein Tyrosine Phosphatase Publishing Receptor Protein-Tyrosine Kinases Regulation Reporting Role STAT5A gene Sampling Scientist Somatic Mutation Specimen Survival Rate Testing Therapeutic Tyrosine United States Vascular Endothelial Growth Factor Receptor-1 Xenograft Model base in vivo inhibitor/antagonist kinase inhibitor leukemia leukemogenesis mortality mutant new therapeutic target novel outcome forecast public health relevance rho rho GTP-Binding Proteins statistics

Acute Myelocytic Leukemia Acute leukemia Adult Adult Acute Myeloblastic Leukemia Age-Years Amino Acids BAY 54-9085 Binding Bone Marrow Cells Clinical Trials Data Development Disease Drops Elderly FLT3 gene Family Genes Genetic Growth Guanosine Triphosphate Phosphohydrolases Hematopoietic High Dose Chemotherapy Human In Vitro Incidence Individual Investigation Ligands Molecular Mononuclear Mutate Mutation Myelogenous Myeloid Leukemia Myeloproliferative disease Nuclear PTPN11 gene Pathogenesis Patients Phenylalanine Population Process Protein Tyrosine Phosphatase Publishing Receptor Protein-Tyrosine Kinases Regulation Reporting Role STAT5A gene Sampling Scientist Somatic Mutation Specimen Survival Rate Testing Therapeutic Tyrosine United States Vascular Endothelial Growth Factor Receptor-1 Xenograft Model base in vivo inhibitor/antagonist kinase inhibitor leukemia leukemogenesis mortality mutant new therapeutic target novel outcome forecast public health relevance rho rho GTP-Binding Proteins statistics

展开

项目摘要

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a lethal disease which dramatically increases in incidence in individuals >65 years of age, the fastest growing population in the United States. Regrettably, the 5 year survival rate drops dramatically in patients over 65 years (4.3%) compared to patients less than 65 years (34.45%). These dismal statistics have led scientists to investigate the molecular mechanism(s) underlying the transforming process leading to AML in an effort to develop novel, molecularly-targeted, effective, and less toxic therapies for use in this lethal disease. Internal tandem duplications (ITD), an in-frame mutation leading to insertion or duplication of several amino acids near the juxtamembrane domain, in fms-like tyrosine kinase receptor (FLT3), are seen in nearly 25% of all AML patients and confer a poor prognosis. Expression of the Shp2 protein tyrosine phosphatase is consistently elevated in primary leukemia cell specimens from multiple adult acute leukemias compared to Shp2 levels in bone marrow mononuclear cells from healthy controls. However, how Shp2 contributes to myeloid leukemogenesis is unknown. We present preliminary studies demonstrating that Shp2 is constitutively associated with FLT3 in mutant N51-FLT3- and N73-FLT3-bearing cells and that genetic disruption of Shp2 and pharmacologic inhibition of Shp2 preferentially reduces N51-FLT3-induced hyperproliferation compared to that observed in WT FLT3-bearing cells. As a corollary, since Shp2 has been shown to regulate the activation of the Rac subfamily of Rho-GTPases in hematopoietic cells, we predicted that Rac1 and/or Rac2 may also be relevant effectors of FLT3-ITDs. Consistently, we present preliminary findings demonstrating that pharmacologic Rac inhibition using NSC23766 or genetic disruption of Rac2 results in significantly reduced N51-FLT3-induced hyperproliferation. Based on our preliminary data, the central role of STAT5 hyperactivation in FLT3-ITD-induced leukemia, and the reported positive roles of Shp2 and Rac1/Rac2 promoting activated STAT5 nuclear accumulation, the central hypothesis of this application is that, mechanistically, Shp2 and Rac1/Rac2 contribute to FLT3-ITD-induced leukemia by facilitating STAT5 nuclear localization and the expression of STAT5-responsive pro-leukemogenic genes. The objectives of this application are to define the consequences of genetic disruption of Shp2 and Rac1/Rac2 on the activation and nuclear localization of STAT5 and on the development of FLT3-ITD-induced myeloproliferative disorder (MPD) in vivo, to examine the efficacy of a Shp2 inhibitor and a Rac1 inhibitor in an AML xenograft model in vivo, and to define the intracellular tyrosines within the juxtamembrane and the duplicated juxtamembrane of FLT3-ITD that contribute to ligand-independent proliferation.

描述（由申请人提供）：急性髓细胞性白血病（AML）是一种致命的疾病，> 65岁的个体的发病率大大增加，是美国增长最快的人群。遗憾的是，与少于65岁的患者相比，65岁以上的患者（4.3％）的患者（34.45％）的5年生存率急剧下降。这些令人沮丧的统计数据使科学家们研究了导致AML的转化过程的分子机制，以开发出新颖的，分子靶向，有效且毒性较小的疗法，用于这种致命疾病。内部串联重复（ITD）是一种近距离酪氨酸激酶受体（FLT3），导致近25％的AML患者和较差的预后可见，导致近距离酪氨酸激酶受体（FLT3）中的几个氨基酸插入或重复的几个氨基酸。与健康对照组的骨髓单核细胞中的SHP2水平相比，来自多个成年急性白血病的原发性白血病细胞标本中SHP2蛋白磷酸酶的表达始终升高。但是，SHP2如何促进髓样白血病发生尚不清楚。我们提出了初步研究，表明SHP2与突变体N51-FLT3-和N73-FLT3携带细胞中的FLT3组成构成相关，并且SHP2的遗传破坏和SHP2的药理抑制优先降低了N51-FLT3诱导的超生产的超细胞，与观察到的细胞相比，SHP2优先降低了SHP2的遗传破坏。作为推论，由于已显示SHP2调节造血细胞中Rho-GTPases的RAC亚家族的激活，因此我们预测RAC1和/或RAC2也可能是FLT3-ITD的相关效应子。一致地，我们提出了初步发现，表明使用NSC23766或RAC2的遗传破坏的药物RAC抑制作用显着降低了N51-FLT3诱导的高增殖。根据我们的初步数据，STAT5过度激活在FLT3-ITD诱导的白血病中的核心作用，以及促进激活STAT5核积累的SHP2和RAC1/RAC2的积极作用，该应用的核心假设是，机械上的SHP2和RAC1/Rac2在FLT3-ITD-ITD-ITAD-ITAT3上的表达方式和RAC2核定型核酸杆菌的表达方式是STAT5响应性促肌发育基因。该应用的目的是定义SHP2和RAC1/RAC2遗传破坏对Stat5激活和核定位的遗传破坏的后果，以及FLT3-ITD诱导的脊髓增生性疾病（MPD）在体内的发展，以检查AM1抑制剂和AM抑制剂INAFT INAFT INAFT INAFT INAFT INAFT INAFT INAFT INAFT INAFT INAFT INAFT INAFT INAFT INAFT XENORGER INAFT的功效。在近去膜内的酪氨酸和flt3-iTD的重复的近去膜，有助于非配体无关增殖。