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是临床上对常规化疗有抵抗力的侵袭性癌症 方案和迫切需要新的治疗方法。该建议研究了 这些血液肿瘤，并通过促进有针对性的发展， 治疗和精准医学来治疗这些难治性癌症。我们的实验室一直在研究T细胞 从两个主要致癌途径的角度来看肿瘤：LIM结构域仅2（LMO 2）途径 和IL 2 RG/JAK 1/3/STAT 5细胞因子信号通路。LMO 2是最常被解除管制的 T细胞急性淋巴细胞白血病中的癌基因。LMO 2编码一种18 kDa的小蛋白， 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 LMO 2的强制表达诱导T-ALL的机制，并发现了关键的白血病前期 通过LMO 2样分化停滞和增强的自我更新强化表型。的 IL 2 RG/JAK 1/3/STAT 5通路是淋巴细胞发育和功能所必需的， 发现在成熟和未成熟的T细胞肿瘤中，这种途径的功能获得是常见的。在 最近令人兴奋的数据，我们的LMO 2和JAK 3工作已经融合在有趣的发现中。突变和基因 表达分析表明，LMO 2过表达和JAK 3激活突变是在细胞中的一致命中。 成熟和未成熟的T细胞肿瘤。结果表明，这两种途径协同诱导T- 细胞转化有趣的是，LMO 2在双阴性T细胞祖细胞中的强制表达诱导了 高度渗透性T细胞白血病但双阳性祖细胞不发展为白血病。同样， 组成型活性突变体JAK 3的表达本身不诱导疾病。我们假设T细胞 如果这两种途径被一致地激活，则转化为白血病或淋巴瘤可能是明显的。 在这个建议中，我们将研究这种协同性的机制基础，以便T细胞白血病和 淋巴瘤在治疗上可能是更好的靶向。在目标1中，我们将研究 在我们的Lmo 2转基因小鼠中使用骨髓转导和移植LMO 2和JAK 3癌基因 小鼠模型在目标2中，我们将分析IL 2 RG/JAK 1/3/STAT 5通路中的信号转导， 白血病和淋巴瘤。在目标3中，我们将测试JAK抑制剂的使用 针对原发性人T细胞肿瘤的研究，并分析与化疗和LMO 2敲低的协同作用。的 目的是为开发新的生物标志物和新的治疗方法奠定基础 基于LMO 2和IL 2 RG/JAK 1/3/STAT 5通路。