CHARACTERIZATION AND TARGETED THERAPY OF T-ALL DEFICIENT FOR PTEN AND INK4A/ARF

描述(申请人提供)：T-急性淋巴细胞白血病/淋巴瘤(T-ALL)是一种侵袭性很强的恶性肿瘤。由于对T-ALL的遗传学和生物学了解不足，T-ALL的靶向分子/途径受到限制。申请者的长期目标是促进T-ALL细胞发育、增殖和存活的分子过程的知识，并将分子靶点的识别转化为更好地治疗T-ALL。抑癌基因PTEN、INK4a和ARF失活是T-ALL中最常见的遗传事件之一。我们推测失活的Pten和Ink4a/Arf肿瘤抑制基因在T-ALL的肿瘤发生中起协同作用。T-ALL的异常分子途径/基因改变，包括某些microRNAs，在T-ALL的发病机制中起一定作用，联合使用NOTCH1和PI3K/mTOR抑制剂进行靶向治疗，而microorRNAs对T-ALL是有效的。我们的初步研究显示，小鼠的T-ALL在遗传、组织学和免疫表型上与人类的T-ALL相似。在目标1中，我们将确定INK4a或Arf缺乏对Pten Null T-ALL发生的影响。我们计划评估1)T-ALL生物学在组织和病理组织学水平和2)确定差异肿瘤抑制基因突变谱是否影响这一效应。在目标2中，我们将从分子上表征Pten和/或Ink4a/Arf缺陷T-ALL。为了实现这一目标，我们将 评估(1)在T-ALL的发病机制中Pten、Pten和Ink4a/Arf、Ink4a/Arf、Pten和Ink4a、Pten和Arf、Ink4a和Arf缺陷的已知关键基因/通路的状态，(2)miR-150和-155在小鼠T-ALL中的表达水平，(3)表达的miR-150和-155的功能后果，以及(4)miR-150和-155在T-ALL发病机制中的相关靶点。在目标3中，我们将评估靶向治疗Pten和/或Ink4a/Arf缺陷T-ALL的效果。我们将确定(1)阻断PI3K/mTOR通路的作用，(2)GSI的作用，(3)PI3K/mTOR抑制剂和GSI对T-ALL模型的联合作用，(4)PI3K/mTOR抑制剂和GSI对人T-ALL的联合作用，(5)恢复miR-155和-150表达对T-ALL的影响。这些研究可能会为T-ALL发病机制中的关键基因提供洞察力，并提供 T-ALL有效靶向治疗的平台。 公共卫生相关性：T-急性淋巴细胞白血病/淋巴瘤(T-ALL)是一种T-淋巴母细胞的恶性肿瘤。然而，常规化疗远远不能令人满意，主要是由于复发/难治性T-ALL。我们将研究关键基因Pten和Ink4a/Arf在T-ALL发病机制中的作用，以及靶向治疗的选择。

DESCRIPTION (provided by applicant): T-acute lymphoblastic leukemia/lymphoma (T-ALL) is a very aggressive malignancy. Targetable molecules/pathways of T-ALL are limited because of an insufficient understanding of its genetics and biology. The applicant's long-term goal is to advance the knowledge of the molecular processes for the development, proliferation and survival of T-ALL cells, and to translate the identification of molecular targets into better treatment of T-ALL. Inactivation of PTEN, INK4a and ARF tumor suppressor genes is among the most frequent genetic events in T-ALL. We hypothesized that inactivated Pten and Ink4a/Arf tumor suppressors cooperate in the tumorigenesis of T-ALL. Aberrant molecular pathway/genetic changes in T-ALL, including certain microRNAs, play a role in the pathogenesis of T-ALL, and combined targeted therapy with NOTCH1 and PI3K/mTOR inhibitors, and micorRNAs is effective for T-ALL. Our preliminary studies revealed the mouse T-ALL resembled the human counterparts genetically, histologically and immunophenotypically. In Aim 1, we will determine the impact of INK4a or Arf deficiency on the development of Pten null T-ALL. We plan to evaluate 1) T-ALL biology at the organismal and patho-histologic levels and 2) to determine if the differential tumor suppressor mutational spectrum impacts this effect. In Aim 2, we will characterize Pten and/or Ink4a/Arf deficient T-ALL molecularly. In this aim, we will evaluate (1) the status of known critical genes/pathways involved in the pathogenesis of T-ALL deficient for Pten, Pten and Ink4a/Arf, Ink4a/Arf, Pten and Ink4a, Pten and Arf, Ink4a, and Arf, (2) The expressions levels of miR-150 and -155 in the mouse T-ALL, (3) Functional consequences of expressed miR-150 and -155, and (4) the pertinent targets of miR-150 and -155 in the pathogenesis of T-ALL. In Aim 3, we will evaluate the effects of targeted therapies on Pten and/or Ink4a/Arf deficient T-ALL. We will determine (1) the effects of blocking PI3K/mTOR pathways, (2) the effects of GSI, and (3) the combinatorial effects of PI3K/mTOR inhibitor and GSI on our T-ALL models, (4) the combinatorial effects of PI3K/mTOR inhibitor and GSI on human T-ALL, and (5) the effects of restoring miR-155 and -150 expressions on T-ALL. These studies will likely provide insight into critical genes in the pathogenesis of T-ALL, and provide a platform for effective targeted therapies of T-ALL. PUBLIC HEALTH RELEVANCE: T-acute lymphoblastic leukemia/lymphoma (T-ALL) is a malignant neoplasm of T-lymphoblasts. However, conventional chemotherapy has been far from satisfactory, predominantly due to recurrent/refractory T-ALL. We will look into the role of criticl genes, Pten and Ink4a/Arf, in the pathogenesis of T-ALL, and options for targeted therapy.