Role of Jak3 in Anaplastic Large Cell Lymphoma

描述（由申请人提供）：项目概述：本资助申请的总体目标是获得发展知识和技能的机会，成为一名独立的内科科学家，有效地将实验室研究转化为临床研究。建立坚实的研究基础是这种方法的关键要素之一。间变性淋巴瘤激酶阳性间变性大细胞淋巴瘤（ALK+ ALCL）是一种T/零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%的患者目前的治疗无效。Janus kinase 3 （Jak3）是一种蛋白酪氨酸激酶，具有与细胞存活和肿瘤发生相关的生物学功能。我们的初步研究表明，Jak3在ALK+ ALCL细胞系中被组成性激活，抑制Jak3会导致细胞凋亡和细胞周期阻滞，从而降低细胞活力。我们的初步研究还表明Jak3和ALK存在物理关联，抑制Jak3会降低ALK激酶的活性。此外，我们发现肿瘤表达活化Jak3的ALK+ ALCL患者的生存率往往低于肿瘤缺乏活化Jak3表达的ALK+ ALCL患者。此外，我们通过显示IL-9受体-(和IL-9在ALK+ ALCL细胞系和大多数人类原发肿瘤中表达，证明了IL-9有助于Jak3的激活。此外，抗il -9中和抗体降低了ALK+ ALCL细胞中活化Jak3的水平和软琼脂集落的形成。我们的初步研究还表明，在ALK+ ALCL细胞系和大多数人类肿瘤中，Jak3的主要生理抑制剂SHP1缺失或基因甲基化。将SHP1转染到ALK+ ALCL细胞可诱导活化的Jak3水平下调。基于这些结果，我们假设Jak3的多水平失调构成性激活在ALK+ ALCL的发病机制中起重要作用。本提案的具体目的是：1)明确Jak3在ALK+ ALCL中的发病作用；2)确定Jak3在ALK+ ALCL患者肿瘤中活化的生物学和临床意义。拟议研究的全球目标是确定Jak3作为ALK+ ALCL患者的潜在治疗靶点；这一目标与安德森癌症中心将新疗法引入临床的使命完全一致。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作为癌症生物学独立研究者的成功职业生涯奠定坚实的基础。与公共卫生相关：ALK+ ALCL是一种侵袭性癌症，通常影响儿童和年轻人。我们的初步结果表明，Jak3酶在ALK+ ALCL的发生和发展中起重要作用。拟议研究的直接目的是验证Jak3作为这种可怕疾病患者的治疗靶点。

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.