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）是儿童中最常见的癌症形式。 虽然在治疗患有这种癌症的儿童方面取得了实质性进展，但复发性B-ALL仍然是一种严重的疾病。 是儿童癌症死亡人数最多的地区。B-ALL在成人中不太常见，但他们的 预后差得多（~40%存活）。因此，B-ALL仍然是一个重大的健康挑战。实质性 现在有证据表明JAK/STAT 5通路的激活与B-ALL的发展有关。 同样地，编码B细胞所需的转录因子网络的基因中的单等位基因缺失也是可能的。 包括IKZF 1、PAX 5和EBF 1在内的多种细胞因子在人类B-ALL中经常观察到。我们之前 建立了STAT 5激活与前BCR途径中的缺陷合作，最终影响了 包括PAX 5、EBF 1、PU. 1、IRF 4和IKZF 1（下文统称）的转录因子网络 作为PEPII因子）以启动转化。因此，我们的研究结果表明，保持适当的 STAT 5活化和PEPII因子之间的平衡对于引导正常B细胞分化是重要的 和阻止B细胞转化。一个关键的问题仍然是这两个相反的转录 网络的功能是控制B细胞的发育和白血病的发生。我们的初步研究表明， STAT 5和PEPII与超级增强子内的附近位点结合，并招募相反的表观遗传修饰剂，如 如组蛋白乙酰转移酶（HAT）和脱乙酰酶（HDAC）。额外的初步ChIP-Seq数据显示， STAT 5和染色质重塑剂BRG 1在多个增强子处的共定位。我们建议 通过STAT 5和PEPII因子募集特异性HAT、HDACS和染色质重塑 以促进正常B细胞发育的方式依次改变增强子景观。 因此，我们的基本假设是STAT 5和PEPII转录网络参与了 仔细协调的反馈回路，以确保适当的祖B细胞扩增， 随后退出细胞周期，分化为小的前B细胞阶段。我们进一步建议 这个网络中的扰动会导致转变。这些假设将在 以下两个具体目标：（1）建立STAT 5改变增强子景观的机制 在B细胞发育和转化过程中，以及（2）确定STAT 5和PEPII因子如何调节 在B细胞分化和转化过程中的癌基因。这些目标的成功实现， 两个相反的转录网络如何控制正常的B细胞发育， 该网络允许最初的祖B细胞转化以及随后的逆转， 转化过程

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.