INDUCED LEUKEMIC CELL DIFFERENTIATION TO DENDRITC CELL

描述：（改编自申请人摘要）：树突状细胞（DC）是骨 骨髓来源的专职抗原呈递细胞（APC）， 在启动和控制原发性免疫反应中的核心作用，通过 与T和B细胞的同源相互作用。在临床上， DC免疫刺激能力已经转化为重要的前景， 针对实体和血液恶性肿瘤的“细胞疫苗”。一个这样 方法是将白血病原始细胞分化为DC，并使用这些DC 诱导自体抗肿瘤CTL活性。在正常的人类造血过程中， 树突状细胞是一种异质性群体， 造血祖细胞（BPC）沿着不同的分化途径。 不同的细胞外细胞因子和细胞内信号触发DC 体外分化。关于这一点，我们所知甚少。 白血病与这种DC分化信号的关系。关于这一点，我们知道的更少。 在正常或白血病细胞中由这些信号触发的细胞内机制 细胞本申请的假设是，未分化和髓样 白血病细胞保留了分化为免疫刺激细胞的能力， 树突状细胞对特定信号的反应。此外，白血病细胞 在骨髓分化的不同阶段被阻止的细胞将具有不同的 触发DC微分所需的信号要求。对于每个阶段 髓样分化的特异性细胞内信号通路， 整合细胞外刺激将调节DC的不同成分， 分化和功能。此应用程序的总体目标是 双重的：1）。定义和表征诱导白血病细胞的机制 进行DC分化，作为细胞免疫疗法的潜在用途， 疫苗（2）。为了更广泛地了解细胞内 正常DC分化的信号传导和遗传事件， 功能本申请的具体目的和方法是：1）。 确定白血病的特征， 分化成树突状细胞，以及需要哪些信号，2）。 确定哪些细胞内信号通路整合了 启动树突状细胞的细胞外/受体介导的刺激 分化，以及分化/功能的组成部分 （3）哪些途径起作用？分析这些分子的组成 细胞内信号传导途径，以及4）。识别核/遗传事件 由DC分化特异性信号通路调节， 功能

DESCRIPTION: (Adapted from applicant's abstract): Dendritic cells (DC) are bone marrow-derived professional antigen presenting cells (APC) which play the central role in initiating and controlling the primary immune response, via cognate interactions with T and B cells. Clinically, the potent immuno-stimulatory capacity of DC has translated into significant promise as "cellular vaccines" against solid and hematologic malignancies. One such approach is to differentiate leukemic blasts into DC, and use these DC to induce autologous anti-tumor CTL activity. In normal human hematopoiesis, dendritic cells are a heterogeneous population that arises from distinct hematopoietic progenitor cells (BPC) along distinct differentiation pathways. Different extra-cellular cytokines and intra-cellular signals trigger DC differentiation in vitro. Relatively little is known about the response of leukemias to such DC differentiation signals. Even less is known about the intracellular mechanisms triggered by these signals in normal or leukemic cells. The hypothesis of this application is that undifferentiated and myeloid leukemia cells retain the ability to differentiate into immuno-stimulatory dendritic cells in response to specific signals. Additionally, leukemic cells arrested at differing stages of myeloid differentiation will have different signal requirements necessary to trigger DC differentiation. And for each stage of myeloid differentiation, the specific intracellular signaling pathways that integrate the extra-cellular stimuli will regulate distinct components of DC differentiation and function. The overall goals of this application are twofold: 1). To define and characterize mechanisms that induce leukemic cells to undergo DC differentiate for potential use in immunotherapy as cellular vaccines" and 2). To gain a broader understanding of the intracellular signaling and genetic events that underlie normal DC differentiation and function. The specific aims and approach of this application are to: 1). Establish the characteristics of leukemias that can be triggered to differentiate into dendritic cells, and what signals are required, 2). Determine which intracellular signaling pathways integrate the extra-cellular/receptor-mediated stimuli that initiate dendritic cell differentiation, and what component(s) of differentiation/function are regulated by which pathways, 3). Characterize the molecular components of these intracellular signaling pathways, and 4). Identify the nuclear/genetic events regulated by DC differentiation-specific signaling pathways, and their function.