Pathway Dependence on Tyrosine Kinase TYK2 in T-cell Acute Lymphoblastic Leukemia

描述（由申请人提供）：胸腺细胞转化是由特定遗传异常的组合引起的，导致对白血病T细胞的细胞增殖、存活和克隆扩增所独特需要的特定致癌途径的依赖。在T细胞急性淋巴细胞白血病（T-ALL）中识别这种“通路依赖性”和关键的遗传异常将为开发这种疾病的新型靶向治疗提供有希望的候选人。我们的初步数据是用高度创新的“功能丧失”RNA干扰筛选技术产生的，我们发现TYK 2（JAK家族酪氨酸激酶）的丧失对来自T-ALL细胞系和原发性T-ALL样本的白血病细胞是致命的。我们发现TYK 2蛋白在许多T-ALL细胞系中被组成性激活，并且这些细胞通过诱导凋亡对小分子JAK/TYK 2抑制剂敏感。这些结果暗示了对该基因的特定“途径依赖性”，以及来自大多数T-ALL的细胞对TYK 2信号转导途径的重要作用。该提案的目的可以概括为：（i）描述T-ALL中TYK 2通路的组成部分以及T-ALL细胞依赖该通路存活的基础，以及（ii）在临床前模型中鉴定最有前途的小分子TYK 2抑制剂，作为开发T-ALL新型治疗方法的长期目标的第一步。这些目标将通过三个具体目标实现。在目标1中，我们将阐明激活T-ALL中TYK 2通路的分子机制。在目标2中，我们将评估体外抑制TYK 2的先导化合物的有效性。在目标3中，我们将研究T-ALL细胞对小鼠正向移植和原代移植模型中优先的小分子TYK 2抑制剂的体内敏感性。 博士Takaomi Sanda是Dana-Farber癌症研究所（DFCI）儿科肿瘤学系的讲师，在白血病研究领域国际公认的领导者托马斯Look博士的指导下工作。在Sanda博士在日本接受的医学和科学培训的基础上，他发现并正在定义酪氨酸激酶在癌症/白血病细胞增殖和存活中的作用。Look博士经过验证的指导，加上DFCI和附属机构研究界提供的严格和培育的科学环境，为Sanda博士在获奖期间作为讲师和过渡到成为独立研究者的成功提供了最大的机会。

DESCRIPTION (provided by applicant): Thymocyte transformation is caused by combinations of particular genetic abnormalities, leading to a dependence on specific oncogenic pathways that are uniquely required for cell proliferation, survival and clonal expansion of leukemic T-cells. Identifying such "pathway dependence" and critical genetic abnormalities in T-cell acute lymphoblastic leukemia (T-ALL) will reveal promising candidates for the development of novel targeted therapies for this disease. Our preliminary data was generated with the highly innovative technology of a "loss-of-function" RNA interference screen, and we found that loss of TYK2, a JAK family tyrosine kinase, was lethal to leukemic cells from T-ALL cell lines and primary T-ALL samples. We discovered that the TYK2 protein is constitutively activated in manyof T-ALL cell lines, and that these cells are sensitive to a small molecule JAK/TYK2 inhibitor through the induction of apoptosis. These results imply a specific "pathway dependence" on this gene and an essential role for the TYK2 signal transduction pathway by cells from the majority of T-ALLs. The objectives of this proposal can be summarized as: (i) to delineate the components of the TYK2 pathway in T-ALL and the basis for the dependence of T-ALL cells on this pathway for cell survival, and (ii) to identify the most promising small molecule TYK2 inhibitors in preclinical models as a first step toward the long-range goal of developing a novel therapeutic approach in T-ALL. These objectives will be achieved through three specific aims. In Aim 1, we will clarify the molecular mechanisms that activate the TYK2 pathway in T-ALL. In Aim 2, we will evaluate the effectiveness of lead compounds that inhibit TYK2 in vitro. In Aim 3, we will study the in vivo sensitivity of T-ALLcells to prioritized small molecule TYK2 inhibitors in murine orthograft and primagraft models. Dr. Takaomi Sanda is an instructor in the Department of Pediatric Oncology at the Dana-Farber Cancer Institute (DFCI) working under the mentorship of Dr. Thomas Look, an internationally recognized leader in the field of leukemia research. Building on Dr. Sanda's medical and scientific training in Japan, he has uncovered and is now defining the role of tyrosine kinases in the proliferation and survival of cancer/leukemia cells. Dr. Look's proven mentorship coupled with the rigorous and nurturing scientific environment offered by the research community at DFCI and affiliated institutions offer the maximal opportunity for Dr. Sanda's success during the award period as an instructor and in his transition to becoming an independent investigator.