Deciphering miRNA regulated networks controlling the Myc-PI3K crosstalk in B cells and lymphoma

MicroRNAs(MiRNAs)是一种非编码RNA，是细胞命运的重要调节因子。在B细胞谱系中，小RNA控制着正常和恶性细胞的分化和存活。在淋巴瘤的发病机制中，它们与癌基因合作，支持疾病的发展、维持和进展。最近，我们证实了转录因子c-Myc(Myc)和磷脂酰肌醇3-激酶(PI3K)信号通路在Burkitt淋巴瘤发展中的协同作用。Burkitt淋巴瘤是一种起源于生发中心的侵袭性B细胞淋巴瘤。根据我们小组的观察，我们推测miRNA放松调控促进了这两个因素的转化效应。因此，在拟议的项目中，我们将重点研究影响成熟B细胞淋巴瘤Myc-PI3K串扰的miRNA网络的鉴定和特征。基于与人类淋巴癌非常相似的新产生的小鼠模型，对代表未转化对应物的肿瘤细胞和抗原激活的B细胞中的miRNA网络进行了评估。小鼠的数据将得到在人类原发淋巴瘤样本中的发现的补充，我们为此与临床合作伙伴建立了强有力的合作。总之，我们的分析将显著提高我们对淋巴瘤分子发病机制的了解，并可能在不久的将来导致创新的治疗策略。

MicroRNAs (miRNAs) are non-coding RNAs which are important regulators of cell fate. In the B cell lineage the small RNAs control the differentiation and survival of normal and malignant cells. During lymphoma pathogenesis they cooperate with oncogenes to support the development, maintenance and progression of the disease. Recently, we have demonstrated a synergistic effect between the transcription factor c-Myc (Myc) and the phosphatidylinositol 3-kinase (PI3K) signaling pathway in Burkitt lymphoma development, an aggressive B cell lymphoma with germinal center origin. Based on observations in our groups, we speculate that miRNA deregulation promotes the transforming effect of both factors. Thus, in the proposed project we will focus on the identification and characterization of miRNA networks which impact on the Myc-PI3K crosstalk in mature B cell lymphomas. Based on newly generated mouse models that very closely resemble human lymphomagenesis the miRNA networks are evaluated in tumor cells and antigen activated B cells that represent the non-transformed counterpart. The mouse data will be complemented by findings in primary human lymphoma samples for which we established strong collaborations with clinical partners. In summary, our analyses will significantly improve our knowledge of the molecular pathogenesis of lymphomas and might also lead to innovative therapeutic strategies in the near future.