STAT5 in B cell Acute Lymphoblastic Leukemia

项目摘要 祖细胞B细胞急性淋巴细胞白血病（B-ALL）是儿童癌症的最常见形式。新 治疗已经大大改善了这种类型的癌症的预后，但复发性B-ALL仍然是一个危险因素。 是儿童和年轻人死亡的主要原因因此，B-ALL仍然是一个重大的健康挑战。 目前，JAK/STAT 5通路的激活与B-ALL的发展密切相关。同样地， 编码B细胞发育所需的转录因子网络的基因，包括IKZF 1、PAX 5和 EBF 1，在B-ALL中经常以较低水平表达，这是由于编码这些基因的等位基因之一缺失所致。 转录因子我们的实验室已经表明，STAT 5激活与前BCR中的缺陷合作， 信号通路，包括PAX 5、EBF 1、PU.1、IRF 4和IKAROS（统称为PEPII因子 （后文）开始转化。因此，这些研究结果表明， STAT 5活化和PEPII因子对于引导正常B细胞分化和预防B 细胞转化从这些结果中出现的一个关键问题是STAT 5激活如何改变靶点。 基因表达。我们的数据表明，活性磷酸化STAT 5可以与靶基因结合， 激活关键癌基因，同时抑制肿瘤抑制基因。然而，这一机制 发生的情况尚不清楚。根据先前的研究和初步数据，STAT 5可以与 共激活子，如EP 300和CREBBP，以及共阻遏子，如NCOR 1和NCOR 2。我在此 我们提出，募集EP 300而不是CREBBP对于STAT 5诱导转录至关重要。 关键癌基因我进一步提出，STAT 5与NCOR 1和NCOR 2阻遏物的相互作用， STAT 5复合物是肿瘤抑制基因依赖性抑制所必需的。因此，我的中央 一种假说是，需要适当STAT 5转录网络来促进正常B细胞 该网络发展和扰动可导致B细胞转化。这些假设 将在以下两个具体目标中进行测试：（1）建立STAT 5调节 关键癌基因的转录，和（2）建立STAT 5如何抑制关键肿瘤抑制因子的转录， 前体B细胞白血病中的基因。这些目标的完成将进一步促进我们对 STAT 5如何激活和抑制转录，以及这些功能的后续干扰 可以导致B-ALL的转化。

Project Abstract Progenitor B cell acute lymphoblastic leukemia (B-ALL) is the most common form of childhood cancer. New therapies have substantially improved the prognosis of this type of cancer, yet relapsed B-ALL remains a leading cause of death in children and young adults. Thus, B-ALL remains a significant health challenge. Currently, activation of the JAK/STAT5 pathway is strongly implicated in the development of B-ALL. Likewise, genes encoding a network of transcription factors required for B cell development, including IKZF1, PAX5, and EBF1, are frequently expressed at lower levels in B-ALL due to deletions in one of the alleles encoding these transcription factors. Our lab has shown that STAT5 activation cooperates with defects in the pre-BCR signaling pathway, including PAX5, EBF1, PU.1, IRF4, and IKAROS (collectively referred to as PEPII factors hereafter) to initiate transformation. Therefore, these findings demonstrated that proper balance between STAT5 activation and PEPII factors is important for entraining normal B cell differentiation and preventing B cell transformation. One key question that emerges from these results is how STAT5 activation can alter target gene expression. Our data suggests that active phosphorylated STAT5 can bind to target genes and both activate key oncogenes while repressing tumor suppressor genes. However, the mechanism by which this occurs remains unclear. Based on previous studies and preliminary data, STAT5 can associate with co-activators, such as EP300 and CREBBP, and with co-repressors, such as NCOR1 and NCOR2. I hereby propose that the recruitment of EP300 but not CREBBP is critical for STAT5 to induce transcription of key oncogenes. I further propose that the interaction of STAT5 with the NCOR1 and NCOR2 repressor complex is required for STAT5- dependent repression of tumor suppressor genes. Thus, my central hypothesis is that a proper STAT5 transcriptional network is required for promoting normal B cell development and that perturbation of this network can lead to B cell transformation. These hypotheses will be tested in the following two specific aims (1) Establish the mechanism by which STAT5 regulates the transcription of key oncogenes, and (2) Establish how STAT5 represses transcription of key tumor suppressor genes in progenitor B cell leukemia. The completion of these aims will further advance our understanding of how STAT5 both activates and represses transcription and how subsequent perturbation of these functions can lead to transformation in B-ALL.