Pre-BCR and STAT5 Signaling in Acute Lymphoblastic Leukemia

项目摘要 祖细胞B细胞急性淋巴细胞白血病(B-ALL)是儿童最常见的癌症形式。 尽管在治疗患有这种形式的癌症的儿童方面取得了实质性进展，但复发的B-ALL仍然 是儿童因癌症死亡人数最多的原因。B-ALL在成年人中不太常见，但他们的 预后更差(存活率约40%)。因此，B-ALL仍然是一个重大的健康挑战。相当可观 目前有证据表明，JAK/STAT5通路的激活与B-ALL的发生有关。 同样，编码B细胞所需转录因子网络的基因的单等位基因缺失 在人类B-ALL中经常观察到包括IKZF1、PAX5和EBF1在内的发育。我们之前 证实STAT5激活与BCR前通路中的缺陷协同作用，该缺陷最终影响到 包括PAX5、EBF1、PU.1、IRF4和IKZF1(以下统称)的转录因子网络 作为PEPII因子)来启动转化。因此，我们的研究结果表明，保持适当的 STAT5激活和PEPII因子之间的平衡对促进正常B细胞分化非常重要 并防止B细胞转化。一个关键的问题是，这两个对立的转录是如何 网络起着控制B细胞发育和白血病发病的作用。我们的初步研究表明 Stat5和PEPII结合到超级增强子内的附近位置，并招募相反的表观遗传修饰物，如 如组蛋白乙酰转移酶(HATS)和脱乙酰酶(HDACs)。额外的初步芯片-序列数据显示 STAT5和染色质重构体BRG1在多个增强子上的共定位。我们建议 STAT5和PEPII因子对特定HATS、HDAC和染色质重构体的招募 以一种促进正常B细胞发育的方式顺序改变增强子的格局。 因此，我们的基本假设是STAT5和PEPII转录网络参与了 精心安排的反馈循环，以确保适当的祖细胞B细胞扩增，以及 随后从分化的细胞周期退出，进入小的前B细胞阶段。我们进一步建议 这个网络中的扰动导致了转变。这些假设将在 以下两个具体目标：(1)建立STAT5改变增强剂格局的机制 在B细胞发育和转化过程中，以及(2)确定STAT5和PEPII因子如何调节 B细胞分化转化过程中的癌基因。这些目标的成功实现将照亮 两个相反的转录网络如何发挥作用来控制正常的B细胞发育以及如何扰乱 该网络允许祖细胞B细胞的初始转化以及随后的逆转 转型过程。

Project Summary Progenitor B cell acute lymphoblastic leukemia (B-ALL) is the most common form of cancer in children. Although substantial progress has been made in treating children with this form of cancer, relapsed B-ALL still accounts for the highest number of childhood deaths due to cancer. B-ALL is less common in adults but their prognosis is much poorer (~40% survival). Thus, B-ALL remains a significant health challenge. Substantial evidence now exists that activation of the JAK/STAT5 pathway is associated with the development of B-ALL. Likewise, mono-allelic deletions in genes encoding a network of transcription factors required for B cell development, including IKZF1, PAX5 and EBF1, are frequently observed in human B-ALL. We previously established that STAT5 activation cooperates with defects in a pre-BCR pathway that ultimately impinges on a network of transcription factors including PAX5, EBF1, PU.1, IRF4 and IKZF1 (referred to collectively hereafter as PEPII factors) to initiate transformation. Thus, our findings demonstrated that maintaining appropriate balance between STAT5 activation and PEPII factors is important for entraining normal B cell differentiation and preventing B cell transformation. A key question that remains is how these two opposing transcriptional networks function to govern B cell development and leukemia initiation. Our preliminary studies suggest that STAT5 and PEPII bind to nearby sites within super-enhancers and recruit opposing epigenetic modifiers, such as histone acetyltransferases (HATs) and deacetylases (HDACs). Additional preliminary ChIP-Seq data show co-localization between STAT5 and the chromatin remodeler BRG1 at multiple enhancers. We propose that recruitment of specific HATs, HDACS and chromatin remodelers by STAT5 and PEPII factors sequentially alters the enhancer landscape in a manner that promotes normal B cell development. Thus, our underlying hypothesis is that STAT5 and the PEPII transcriptional network are involved in carefully orchestrated feedback loops to ensure both appropriate progenitor B cell expansion, and subsequent exit from cell cycle with differentiation to the small pre-B cell stage. We further propose that perturbations in this network lead to transformation. These hypotheses will be explored in the following two specific aims: (1) Establish the mechanism by which STAT5 alters the enhancer landscape during B cell development and transformation, and (2) Establish how STAT5 and PEPII factors regulate oncogenes during B cell differentiation and transformation. Successful completion of these aims will illuminate how two opposing transcriptional networks function to govern normal B cell development and how perturbing that network allows for both initial progenitor B cell transformation as well as subsequent reversal of the transformation process.