Gadd45 stress sensors in leukemia

白血病中的 Gadd45 应激传感器

• 批准号: 8623106
• 负责人: DAN A LIEBERMANN
• 金额: $ 30.8万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623106
• 关键词: AML/MDS; Apoptosis; Biological; Breast Carcinogenesis; CRKL gene; Cancer Model; Cell Cycle Arrest; Cell Proliferation; Cell Survival; Cells; Chronic Myeloid Leukemia; Complex; Cytoskeleton; DNA Repair; Data; Development; Disease; Disease Progression; Effector Cell; Event; Exhibits; Frequencies; GAB2 gene; GRB2 gene; Gene Family; Genes; Genome Stability; HRAS gene; Hematopoietic Neoplasms; Human; Imatinib; In Vitro; Incidence; Inflammatory Response; KRAS2 gene; Knowledge; Laboratories; Malignant Neoplasms; Mediator of activation protein; Messenger RNA; Modality; Molecular; Multiple Myeloma; Mus; Mutation; Myelogenous; Myeloproliferative disease; NRAS gene; Natural Immunity; Nature; Nuclear Proteins; Oncogene Proteins; Oncogenes; Oncogenic; Outcome; Pathogenesis; Pathway interactions; Patients; Personal Communication; Phosphotransferases; Physiological; Play; Protein Tyrosine Kinase; Proteins; Research; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; Staging; Stress; Translating; Tumor Promoters; Tumor Suppressor Proteins; adapter protein; bcr-abl Fusion Proteins; biological adaptation to stress; cancer initiation; cancer therapy; cell type; cytokine; environmental stressor; gain of function; improved; in vivo; leukemia; leukemogenesis; molecular pathology; mouse model; novel; response; senescence; sensor; stressor; tumor progression

DESCRIPTION (provided by applicant): Gadd45 family of genes (Gadd45a, b, g) encode for cellular proteins rapidly induced by multiple stressors, including genotoxic & oncogenic stress. The unique role of Gadd45 proteins as sensors of oncogenes has been born out by several novel cancer mouse models in this laboratory, indicating that, dependent on the activated oncogene, gadd45 can function as either tumor promoter or suppressor by tethering distinct signaling pathways. Gadd45 has been identified as a mediator of oncogenic ras signaling. Ras mutations occur frequently in hematopoietic malignancies, including in AML, MPD and MDS. Recent evidence indicates that oncogenic N-RAS, K-RAS, and H- RAS exhibit different leukemogenic potentials in mice, suggesting that myeloid leukemogenesis by oncogenic RAS involves unique RAS signaling networks that need to be determined. On the other hand, BCR-ABL (BA) is known as the most common translocation in the myeloproliferative (MPD) disorder chronic myelogenous leukemia (CML) where an activated BA kinase oncoprotein impacts on cell proliferation and survival signaling pathways including Ras, PI3K, JAK-STAT, and PDk2-NFkB. The complex nature of these signaling pathways in the pathogenesis of CML is not fully understood. Recently Gadd45a expression was documented to be altered in a subset of AML patients. Our preliminary data indicate that Gadd45a behaves as an oncogene in context of N-RAS driven leukemia whereas both Gadd45a & b function as tumor suppressors in context of BA-driven leukemia. Also, Gadd45a,b expression was observed to be altered in human CML correlating with disease progression. The role of Gadd45 proteins as oncogenic stress sensors that modulate oncogene driven leukemias has not been studied, and understanding the role of these novel modulators in the molecular pathology of RAS and BCR-ABL is important. To this end, two Specific Aims are delineated: Aim 1 is targeted at assessing how Gaddd45a modulates RAS driven leukemogenicity. Sub-aim 1A will ascertain the effect of loss of Gadd45a on RAS-driven leukemic transformation in vivo~ Sub-aim 1B is targeted at studying the effect of loss of Gadd45a in BM expressing oncogenic RAS in vitro~ finally Sub-aim 1C will analyze human AML/MDS for activated RAS, alterations in Gadd45a and genes/pathways regulated by altered Gadd45a function. Aim 2 is targeted at exploring how Gaddd45a,b tumor suppressor functions impact on BA-driven leukemia and signaling. Sub-aim 2A will ascertain the effect of loss of Gadd45a & b function on BA-driven leukemia and Imatinib treatment~ Sub-aim 2B will explore how loss of Gadd45a and Gadd45b impact on BA oncogenic potential and imatinib treatment in vitro~ Sub-aim 2C will ascertain how gain of function of Gadd45a or b in primary BM impacts on BA oncogenic effect and imatinib treatment~ and, finally, Sub-aim 2D will analyze human CML for alterations in Gadd45a and Gadd45b and genes/pathways differentially regulated by altered function of Gaddd45a & Gadd45b. Knowledge gained from the proposed research should influence understanding of leukemogensis as well as add to the understanding of the role stress response genes play in other cancers, and contribute to the development of new/improved modalities for treatment of cancer.

描述（由申请人提供）：Gadd45家族基因（Gadd45a, b, g）编码多种应激源（包括遗传毒性和致癌应激）快速诱导的细胞蛋白。Gadd45蛋白作为癌基因传感器的独特作用已经在该实验室的几个新型癌症小鼠模型中得到证实，表明依赖于激活的癌基因，Gadd45可以通过拴住不同的信号通路作为肿瘤启动子或抑制子。Gadd45已被确定为致癌ras信号的中介。Ras突变经常发生在造血恶性肿瘤中，包括AML、MPD和MDS。最近的证据表明，致癌基因N-RAS、K-RAS和H- RAS在小鼠中表现出不同的致白血病潜能，这表明致癌基因RAS发生髓性白血病涉及独特的RAS信号网络，有待确定。另一方面，BCR-ABL （BA）被认为是骨髓增生性（MPD）疾病慢性髓性白血病（CML）中最常见的易位，其中活化的BA激酶癌蛋白影响细胞增殖和存活信号通路，包括Ras， PI3K， JAK-STAT和PDk2-NFkB。这些信号通路在CML发病机制中的复杂性质尚不完全清楚。最近，Gadd45a的表达在AML患者的一个亚群中发生了改变。我们的初步数据表明，Gadd45a在N-RAS驱动的白血病中表现为癌基因，而Gadd45a和b在ba驱动的白血病中都表现为肿瘤抑制基因。此外，Gadd45a，b的表达在人类CML中被观察到与疾病进展相关。Gadd45蛋白作为调节癌基因驱动的白血病的致癌应激传感器的作用尚未得到研究，了解这些新型调节剂在RAS和BCR-ABL的分子病理学中的作用是重要的。为此，研究人员描述了两个特异性目的：目的1旨在评估Gaddd45a如何调节RAS驱动的白血病发生。Sub-aim 1A将确定Gadd45a缺失对体内RAS驱动的白血病转化的影响；Sub-aim 1B旨在研究体外表达癌性RAS的BM中Gadd45a缺失的影响；最后Sub-aim 1C将分析人类AML/MDS中活化的RAS、Gadd45a的改变以及Gadd45a功能改变所调节的基因/途径。Aim 2旨在探索gadd45a，b肿瘤抑制功能如何影响ba驱动的白血病及其信号传导。Sub-aim 2A将确定Gadd45a和b功能丧失对BA驱动的白血病和伊马替尼治疗的影响；Sub-aim 2B将探索Gadd45a和Gadd45b功能丧失如何影响BA的致癌潜力和体外伊马替尼治疗；Sub-aim 2C将确定原发性BM中Gadd45a或b功能的获得如何影响BA的致癌作用和伊马替尼治疗；Sub-aim 2D将分析人类CML中Gadd45a和Gadd45b以及受Gadd45a和Gadd45b功能改变差异调节的基因/途径的改变。从拟议的研究中获得的知识应该影响对白血病发生的理解，并增加对应激反应基因在其他癌症中所起作用的理解，并有助于开发新的/改进的癌症治疗方式。