The Protein Kinase C Pathway In Acute Leukemia

急性白血病中的蛋白激酶 C 通路

• 批准号: 7616072
• 负责人: Amanda J Redig
• 金额: $ 4.62万
• 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: 2007-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616072
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Aromatic Hydrocarbons; Benzene; Benzene Exposure; Blood; Bone Marrow; Carcinogens; Cell Proliferation; Chemicals; Development; Environmental Carcinogens; Environmental Exposure; Environmental Pollutants; Equilibrium; Erythropoiesis; Event; Exhibits; Exposure to; Family; Functional disorder; Growth; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Lead; Myelopoiesis; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Phosphotransferases; Play; Prevention therapy; Process; Production; Property; Protein Family; Protein Isoforms; Protein Kinase C; Protein-Serine-Threonine Kinases; Proteins; Regulation; Role; Staging; Stem cells; Stimulus; Time; cell growth; cellular targeting; citrate carrier; leukemia; leukemogenesis; member; novel; progenitor

DESCRIPTION (provided by applicant): Acute leukemias result when the regulation of the normal hematopoietic process goes awry at the stem cell or progenitor levels. Benzene (BZ) is an aromatic hydrocarbon in widespread use as an industrial chemical, and is known to play a causative role in the development of certain cases of acute myeloid leukemia (AML). The leukemogenic properties of BZ and its metabolites are thought to occur via effects on normal hematopoietic precursors, but the precise cellular events responsible for benzene-induced leukemogenesis remain unknown. One group of proteins that are potential candidates for such causative effects is the protein kinase C (PKC) family of serine-threonine kinases. These kinases are activated by a wide range of stimuli, including BZ and oxidative stress, and exhibit context-dependent and isoform-specific effects on cell proliferation and differentiation. This proposal will examine the expression and functional roles of the PKC family of proteins in normal hematopoiesis and will determine whether abnormalities in the expression of PKC proteins contributes to the development of AML, including AML related to benzene exposure. Specific aim A is to determine the role of the PKC family in normal hematopoiesis. Studies will be performed to define the expression of different PKC-isoforms during early and late stages of normal erythropoiesis and myelopoiesis, and to examine the effects of disruption of their expression or inhibition of their kinase activities on hematopoietic progenitor cell growth and differentiation. Specific aim B is to determine the role of the PKC family in AML. The patterns of expression of PKC members and their contribution to leukemogenesis will be investigated in primary leukemic progenitors from the bone marrows of patients with AML and will be correlated to prior exposure to benzene. Project relevance: Environmental exposures to benzene and other carcinogens can lead to the development of different forms of AML, thus understanding the mechanisms by which such carcinogens promote the onset of leukemic phenotypes is an essential step towards the development of novel therapies and the prevention of such leukemias. Among the known cellular targets of benzene is the PKC family of proteins, but very little is known about the expression and pathogenetic role of these kinases in benzene-related cases of acute leukemia. This proposal is a comprehensive approach to examine the function of PKC isotypes in normal hematopoietic progenitors and to identify abnormalities in their expression in AML, thereby providing valuable information on the mechanisms by which environmental carcinogens promote leukemogenesis and leading to the identification of novel targets for acute leukemia treatment.

描述（由申请人提供）：当正常造血过程的调节在干细胞或祖细胞水平上出现问题时，会导致急性白血病。苯（BZ）是广泛用作工业化学物质的一种芳族碳氢化合物，众所周知，在某些急性髓样白血病（AML）的发展中起着致病作用。 BZ及其代谢产物的白血病特性被认为是通过对正常造血前体的影响而发生的，但是导致苯诱导的白血病发生的精确细胞事件仍然未知。丝氨酸 - 苏氨酸激酶的蛋白激酶C（PKC）家族蛋白激酶C（PKC）家族。这些激酶通过广泛的刺激（包括BZ和氧化应激）激活，并表现出对细胞增殖和分化的上下文依赖性和同工型特异性的影响。该建议将检查PKC蛋白质蛋白在正常造血中的表达和功能作用，并将确定PKC蛋白表达中异常是否有助于AML的发展，包括与苯暴露有关的AML。具体目的A是确定PKC家族在正常造血中的作用。将进行研究，以定义正常红细胞生成和脊髓疾病的早期和晚期中不同PKC-异型的表达，并检查其表达的破坏或抑制其激酶活性对造血祖细胞生长和差异的影响。特定目标B是确定PKC家族在AML中的作用。 PKC成员的表达模式及其对白血病的贡献将在AML患者的骨髓原发性祖细胞中进行研究，并将与事先暴露于苯。项目相关性：对苯和其他致癌物的环境暴露会导致不同形式的AML的发展，从而了解这种致癌物促进白血病表型开始的机制，是迈向新疗法及其预防这种白血病的重要步骤。苯的已知细胞靶标是PKC的蛋白质家族，但对于这些激酶在与苯相关的急性白血病病例中的表达和致病作用知之甚少。该提案是一种综合方法，可以检查PKC同种型在正常造血祖细胞中的功能，并在AML中鉴定其表达异常，从而提供有关环境致癌物促进白血病的机制的有价值的信息，从而促进白血病的作用，并导致对急性白血病治疗的新靶标。

项目成果

Incorporating fertility preservation into the care of young oncology patients.

将保留生育能力纳入年轻肿瘤患者的护理中。

• DOI: 10.1002/cncr.25398
• 发表时间: 2011
• 期刊: Cancer
• 影响因子: 6.2
• 作者: Redig,AmandaJ;Brannigan,Robert;Stryker,StevenJ;Woodruff,TeresaK;Jeruss,JacquelineS
• 通讯作者: Jeruss,JacquelineS

Care of the cancer survivor: metabolic syndrome after hormone-modifying therapy.

• DOI: 10.1016/j.amjmed.2009.06.022
• 发表时间: 2010-01
• 期刊: AMERICAN JOURNAL OF MEDICINE
• 影响因子: 5.9
• 作者: Redig, Amanda J;Munshi, Hidayatullah G
• 通讯作者: Munshi, Hidayatullah G