Role of Jak3 in Anaplastic Large Cell Lymphoma

Jak3 在间变性大细胞淋巴瘤中的作用

• 批准号: 7145244
• 负责人: HESHAM M AMIN
• 金额: $ 13.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145244
• 关键词: cell line; genes; lymphoma; neoplasm /cancer; role

DESCRIPTION (provided by applicant): Project Summary: The overall goal of this grant application is to acquire the opportunity to develop the knowledge and skills to become an independent physician-scientist who effectively translates bench studies to the clinic. Establishing a solid research foundation is one of the key elements with this approach. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) is an aggressive malignant lymphoma of T/null-cell immunophenotype. It frequently affects children and young adults, and an estimated 40-50% of the patients fail current therapeutics. Janus kinase 3 (Jak3) is a protein tyrosine kinase with biologic functions related to cell survival and tumorigenesis. Our preliminary studies showed that Jak3 is constitutively activated in ALK+ ALCL cell lines and that inhibition of Jak3 decreases cell viability due to apoptosis and cell cycle arrest. Our preliminary studies also showed that Jak3 and ALK are physically associated and that inhibition of Jak3 decreases ALK kinase activity. Further, we found that ALK+ ALCL patients with tumors expressing activated Jak3 tend to have a lower survival rate than in ALK+ ALCL patients with tumors lacking the expression of activated Jak3. In addition, we demonstrated that IL-9 contributes to Jak3 activation by showing that IL-9 receptor-( and IL-9 are expressed in ALK+ ALCL cell lines and in most human primary tumors. Moreover, an anti-IL-9 neutralizing antibody decreased levels of activated Jak3 in and soft agar colony formation of ALK+ ALCL cells. Our preliminary studies also demonstrated that a major physiologic inhibitor of Jak3, SHP1, is absent or gene methylated in ALK+ ALCL cell lines and in most human tumors. Transfection of SHP1 into ALK+ ALCL cells induced downregulation of activated Jak3 levels. On the basis of these results, we hypothesize that constitutive activation of Jak3 by multilevel dysregulation plays an important role in the pathogenesis of ALK+ ALCL. The specific aims of this proposal are to 1) define the pathogenetic role of Jak3 in ALK+ ALCL and 2) establish the biologic and clinical significance of Jak3 activation in tumors from ALK+ ALCL patients. The global aim of the proposed studies is to identify Jak3 as a potential therapeutic target in ALK+ ALCL patients; this aim is in complete agreement with the mission of M.D. Anderson Cancer Center of bringing novel therapeutics to the clinic. The balanced program of mentored research and career development proposed in this application will provide the applicant with a solid foundation for a successful career as an independent investigator in cancer biology. Relevance to public health: ALK+ ALCL is an aggressive type of cancer that commonly affects children and young adults. Our preliminary results showed that the enzyme Jak3 plays an important role in the development and progression of ALK+ ALCL. The direct aim of the proposed studies is to validate Jak3 as a therapeutic target in patients afflicted with this dreadful disease.

描述（由申请人提供）：项目摘要：本赠款申请的总体目标是获得发展知识和技能的机会，成为一名独立的医生 - 科学家，他们有效地将基准研究转化为诊所。建立可靠的研究基础是这种方法的关键要素之一。肿瘤性淋巴瘤激酶阳性对偏型大细胞淋巴瘤（ALK+ ALCL）是T/NULL-细胞免疫表型的侵袭性恶性淋巴瘤。它经常影响儿童和年轻人，估计有40-50％的患者失败了当前的治疗剂。 Janus激酶3（JAK3）是一种蛋白酪氨酸激酶，具有与细胞存活和肿瘤发生有关的生物学功能。我们的初步研究表明，JAK3在ALK+ ALCL细胞系中被组成性激活，并且JAK3的抑制会降低由于细胞凋亡和细胞周期停滞而引起的细胞活力。我们的初步研究还表明，JAK3和ALK在物理上相关，JAK3的抑制会降低ALK激酶活性。此外，我们发现表达活化JAK3肿瘤的ALK+ ALCL患者的存活率往往低于缺乏活化JAK3表达的ALK+ ALCL患者。此外，我们证明了IL-9通过表明IL-9受体 - （和IL-9在ALK+ ALCL细胞系和大多数人类原发性肿瘤中表达）来促进JAK3激活。此外，一种抗IL-9中和抗体在ALK+ Alcl Cellimation的抗激活的Jak3水平上降低了ALK+ Alcl incl and primimantiral的抗激活水平。 JAK3 SHP1在ALK+ ALCL细胞系中没有基因甲基，在大多数人类肿瘤中，将SHP1转染到ALK+ ALCL细胞中。定义JAK3在ALK+ ALCL中的致病作用和2）在ALK+ ALCL患者的肿瘤中确定JAK3激活的生物学和临床意义。拟议的研究的全球目的是将JAK3识别为ALK+ ALCL患者的潜在治疗靶点。该目标与M.D. Anderson癌症中心的任务完全同意，该中心将新型治疗剂带到诊所。在本申请中提出的指导研究和职业发展的平衡计划将为申请人提供稳固的基础，以成功地成为癌症生物学独立研究者的职业生涯。与公共卫生有关：ALK+ ALCL是一种侵略性的癌症，通常会影响儿童和年轻人。我们的初步结果表明，JAK3酶在ALK+ ALCL的发展和发展中起重要作用。拟议研究的直接目的是验证JAK3作为患有这种可怕疾病的患者的治疗靶标。