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

描述（由申请人提供）：t -急性淋巴细胞白血病/淋巴瘤（T-ALL）是一种非常具有侵袭性的恶性肿瘤。由于对其遗传学和生物学的了解不足，T-ALL的靶向分子/途径有限。申请人的长期目标是推进对T-ALL细胞发育、增殖和存活的分子过程的了解，并将分子靶点的鉴定转化为更好的T-ALL治疗。PTEN、INK4a和ARF肿瘤抑制基因失活是T-ALL中最常见的遗传事件。我们假设失活的Pten和Ink4a/Arf肿瘤抑制因子在T-ALL的肿瘤发生中协同作用。T-ALL的异常分子通路/遗传改变，包括某些microRNAs，在T-ALL的发病机制中发挥作用，与NOTCH1和PI3K/mTOR抑制剂联合靶向治疗，microRNAs对T-ALL有效。我们的初步研究表明，小鼠T-ALL在遗传、组织学和免疫表型上与人类T-ALL相似。在Aim 1中，我们将确定INK4a或Arf缺乏对Pten null T-ALL发展的影响。我们计划在组织和病理组织学水平上评估1)T-ALL生物学，2)确定不同的肿瘤抑制基因突变谱是否影响这种效应。在Aim 2中，我们将从分子上表征Pten和/或Ink4a/Arf缺陷T-ALL。为此，我们将

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.