Pathophysiology of Adult T-cell Leukemia/Lymphoma

成人 T 细胞白血病/淋巴瘤的病理生理学

• 批准号: 10045553
• 负责人: Utpal P Dave
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-03 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045553
• 关键词: Acute T Cell Leukemia; Adult T-Cell Leukemia/Lymphoma; Advanced Development; Affect; Age Distribution; Apoptosis; Biological Markers; Bone Marrow; Caring; Chemotherapy-Oncologic Procedure; Clinical; Cytokine Activation; Cytokine Signaling; Cytotoxic agent; DNA Sequence Alteration; Data; Development; Disease; Elderly; FDA approved; FLT3 gene; Female; Fibrinogen; Foundations; Functional disorder; Gene Expression Profiling; Genes; Genetic Transcription; Health; Hematologic Neoplasms; Human; IL2RG gene; JAK1 gene; JAK3 gene; LMO2 gene; Laboratories; Lymphocyte Function; Lymphoma; Mutate; Mutation; Myeloid Leukemia; Neoplasms; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation; Proteins; RUNX1 gene; Resistance; Sampling; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stat5 protein; Stimulus; T-Cell Development; T-Cell Leukemia; T-Cell Transformation; T-Cell and NK-Cell Neoplasm; T-Lymphocyte; Testing; Transgenic Mice; Transplantation; Tumor stage; Veterans; Work; base; chemotherapy; driver mutation; drug sensitivity; experience; gain of function; in vivo; inhibitor/antagonist; knock-down; leukemia; leukemia/lymphoma; leukemogenesis; male; military veteran; mouse model; mutant; new therapeutic target; novel marker; novel therapeutic intervention; overexpression; precision medicine; progenitor; protein complex; refractory cancer; self-renewal; stem cells; synergism; targeted biomarker; targeted treatment; therapeutic target; transcription factor; tumor initiation; young adult

T-cell leukemias and lymphomas are clinically aggressive cancers resistant to conventional chemotherapy regimens and in desperate need for novel therapeutic approaches. This proposal studies the pathogenesis of these hematologic neoplasms and directly benefits Veterans' health by advancing the development of targeted therapy, and precision medicine for these treatment-resistant cancers. Our laboratory has been studying T-cell neoplasms from the perspective of two major oncogenic pathways: the LIM domain Only-2 (LMO2) pathway and the IL2RG/JAK1/3/STAT5 cytokine signaling pathway. LMO2 is one of the most frequently deregulated oncogenes in T-cell acute lymphoblastic leukemia. LMO2 encodes a small 18 kDa protein that is part of a large multisubunit protein complex that regulates the transcription of key target genes. We have been dissecting the mechanism by which LMO2's enforced expression induces T-ALL and have discovered key pre-leukemic phenotypes enforced by LMO2 like differentiation arrest and enhanced self-renewal. The IL2RG/JAK1/3/STAT5 pathway is required for the development and function of lymphocytes and our lab discovered that gain of function in this pathway is common in both mature and immature T-cell neoplasms. In recent exciting data, our LMO2 and JAK3 work has converged in intriguing findings. Mutational and gene expression analyses show that LMO2 overexpression and JAK3 activating mutations are concordant hits in both mature and immature T-cell neoplasms. The results imply that these two pathways cooperate to induce T- cell transformation. Interestingly, enforced expression of LMO2 in double negative T-cell progenitors induces highly penetrant T-cell leukemias but double positive progenitors do not develop leukemia. Similarly, enforced expression of constitutively active mutant JAK3 does not induce disease on its own. We hypothesize that T-cell transformation into leukemia or lymphomas may manifest if these two pathways were concordantly activated. In this proposal, we will investigate the mechanistic basis of this cooperativity so that T-cell leukemias and lymphomas may be better targeted therapeutically. In Aim 1, we will investigate the cooperativity between LMO2 and JAK3 oncogenes using bone marrow transduction and transplantation in our Lmo2 transgenic mouse model. In Aim 2, we will analyze signal transduction within the IL2RG/JAK1/3/STAT5 pathway in leukemias and lymphomas induced in Lmo2 transgenic mice. In Aim 3, we will test the use of JAK inhibitors against primary human T-cell neoplasms and analyze synergy with chemotherapy and LMO2 knockdown. The Aims will establish a foundation for the development of novel biomarkers and novel therapeutic approaches based on LMO2 and IL2RG/JAK1/3/STAT5 pathways.

T细胞白血病和淋巴瘤在临床上具有抗癌症的抗性癌症 方案和迫切需要新颖的治疗方法。该建议研究了 这些血液学肿瘤，并通过推进目标的发展而直接使退伍军人的健康受益 这些耐药性癌症的疗法和精确药物。我们的实验室一直在研究T细胞 从两个主要的致癌途径的角度来看肿瘤：仅LIM结构域-2（LMO2）途径 以及IL2RG/JAK1/3/STAT5细胞因子信号通路。 LMO2是最常见的管制之一 T细胞急性淋巴细胞白血病中的癌基因。 LMO2编码一个小的18 kDa蛋白，该蛋白是大型的一部分 调节关键靶基因转录的多亚基蛋白复合物。我们一直在解剖 LMO2强迫表达诱导T-All并发现了关键的leukemictic的机制 LMO2强制执行的表型，例如分化停滞和增强的自我更新。这 IL2RG/JAK1/3/STAT5途径是淋巴细胞开发和功能所必需的 发现在成熟和未成熟的T细胞肿瘤中，该途径中功能的增益都是常见的。在 最近的令人兴奋的数据，我们的LMO2和JAK3工作在有趣的发现中融合了。突变和基因 表达分析表明，LMO2过表达和JAK3激活突变是一致的打击 成熟和未成熟的T细胞肿瘤。结果表明，这两种途径合作诱导T- 细胞转换。有趣的是，在双负T细胞祖细胞中强制表达LMO2会诱导 高度渗透的T细胞白血病，但双重阳性祖细胞不会出现白血病。同样，执行 组成性活跃的突变体JAK3的表达不会自行诱导疾病。我们假设T细胞 如果这两种途径一致激活，则可能体现为白血病或淋巴瘤。 在此提案中，我们将调查这种合作的机械基础，以便T细胞白血病和 淋巴瘤可以更好地靶向治疗。在AIM 1中，我们将研究 LMO2和JAK3癌基因使用骨髓转导和移植在我们的LMO2转基因中 鼠标模型。在AIM 2中，我们将分析IL2RG/JAK1/3/STAT5途径内的信号转导 LMO2转基因小鼠诱导的白血病和淋巴瘤。在AIM 3中，我们将测试JAK抑制剂的使用 针对原代人T细胞肿瘤，并通过化学疗法和LMO2敲低分析协同作用。这 AIMS将为开发新型生物标志物和新型治疗方法建立基础 基于LMO2和IL2RG/JAK1/3/STAT5途径。