Molecular Programs for Stem Cells of Hematological Malignancies

描述（由申请人提供）：已经提出人类癌症含有负责启动和维持肿瘤生长的癌症干细胞（CSC），并且这些干细胞对治疗具有抗性。然而，CSC的概念最近一直受到围攻。有些人认为，这一概念是使用异种模型的人为产物，因为随着使用越来越多的免疫缺陷宿主，引发癌症的细胞的频率似乎急剧增加。也许CSC概念的一个更根本的挑战是CSC的分子程序不一定与癌细胞的主体不同。例如Wnt、Hedgehog和Bmi- 1，它们是已知的CSC自我更新的调节剂，通常也参与细胞增殖的调节。为了克服这些警告，我们一直在使用自发性小鼠淋巴瘤模型来确定CSC功能的分子程序。CSC的两个重要功能，即CSC的自我更新和维护，我们最近的研究，这是接受发表在细胞干细胞，已经建立了CSC维护的分子编程。在这些进展的基础上，我们提出鉴定驱动CSC自我更新的编程，并进一步确定我们是否可以使用这些自我更新和维持程序将癌细胞重编程回CSC。 公共卫生相关性：已经提出，人类癌症含有负责启动和维持肿瘤生长的癌症干细胞（CSC），并且这些癌症干细胞对治疗具有抗性。CSC概念的一个更根本的挑战是CSC的分子程序不一定与癌细胞的主体不同。为了克服这些警告，我们一直在使用自发性小鼠淋巴瘤模型来确定CSC功能的分子程序。CSC的两个重要功能，即CSC的自我更新和维护，我们最近的研究，这是接受发表在细胞干细胞，已经建立了CSC维护的分子编程。在这些进展的基础上，我们提出鉴定驱动CSC自我更新的编程，并进一步确定我们是否可以使用这些自我更新和维持程序将癌细胞重编程回CSC。

DESCRIPTION (provided by applicant): It has been proposed that human cancers contain cancer stem cells (CSC) that are responsible for initiating and maintaining tumor growth and also, these are resistant to therapy. However, the concept of CSC has been under siege recently. Some have argued that the concept is an artifact of using xenogeneic models, as the frequency of cancer-initiating cells appears to increase dramatically with the use of increasingly immune-deficient hosts. Perhaps a more fundamental challenge of the CSC concept is that the molecular program of CSC is not necessarily distinct from the bulk of cancer cells. For instance Wnt, Hedgehog and Bmi- 1, which are known regulators for self-renewal of CSC, are also involved in regulation of cell proliferation in general. To overcome these caveats, we have been using a spontaneous mouse lymphoma model to determine the molecular program underlying CSC functions. Of the two seminal functions of CSC, namely, self-renewal and maintenance of CSC, our recent study, which was accepted for publication in Cell Stem Cell, has established the molecular programming underlying CSC maintenance. Building on these advances, we propose to identify the programming driving CSC self-renewal and further, determine if we can use these self- renewal and maintenance programs to reprogram cancer cells back into CSC. PUBLIC HEALTH RELEVANCE: It has been proposed that human cancers contain cancer stem cells (CSC) that are responsible for initiating and maintaining tumor growth and also, these are resistant to therapy. A more fundamental challenge of the CSC concept is that the molecular program of CSC is not necessarily distinct from the bulk of cancer cells. To overcome these caveats, we have been using a spontaneous mouse lymphoma model to determine the molecular program underlying CSC functions. Of the two seminal functions of CSC, namely, self-renewal and maintenance of CSC, our recent study, which was accepted for publication in Cell Stem Cell, has established the molecular programming underlying CSC maintenance. Building on these advances, we propose to identify the programming driving CSC self-renewal and further, determine if we can use these self- renewal and maintenance programs to reprogram cancer cells back into CSC.