Genomic translocations, super-enhancer hijacking and oncogene activation: from mechanism to therapy

造血是一个发育过程，最终形成我们免疫系统所需的所有血细胞。这个过程中的错误导致细胞在特定分化阶段的积累，导致血液系统恶性肿瘤的发展。基因易位是癌症的一个标志。它们的识别导致了血液系统恶性肿瘤诊断和预后的改善。我们对B淋巴细胞中免疫球蛋白（Ig；抗体）位点易位引起的白血病和淋巴瘤特别感兴趣。产生抗体库需要Ig基因位点及其超级增强子的正常重排，但这些超级增强子可能被癌基因异常重排和“劫持”。然而，我们对这些基因组信息的了解非常有限，利用这些数据的治疗策略还有待开发。超过70个基因被转移到Ig位点，并由于重排而过度表达，但这不是一个随机的过程。反复易位暗示了一种支持特定启动子和增强子之间发育阶段特异性、远距离相互作用的共同机制。一个强有力的候选机制可能是共享转录调控蛋白（TRPs），它可能结合每个位点的调控区域，有利于易位。本项目将开发和应用计算方法，并结合补充的实验室实验来识别正常和恶性人类b细胞发育中的关键TRPs。

Background Haematopoiesis is a developmental process which culminates in the formation of all the blood cells required in our immune system. Errors in this process leads to the accumulation of cells held at a specific stage of differentiation, resulting in the development of haematological malignancies. Genomic translocations are a hallmark of cancer. Their identification has led to improvements in diagnosis and outcome in haematological malignancies. We are particularly interested in leukaemias and lymphomas resulting from translocations in the immunoglobulin (Ig; antibody) locus in B lymphocytes. Normal rearrangement of Ig gene loci and their super-enhancers is needed to generate the antibody repertoire, but these super-enhancers can be aberrantly rearranged and "hijacked" by oncogenes. However, our understanding of this genomic information is very limited and therapeutic strategies exploiting this data are yet to be developed. Over 70 genes are translocated to the Ig loci and overexpressed as a result of the rearrangement, but this is not a random process. Recurrent translocations imply a common mechanism that supports developmental stage-specific, long-range interactions between particular promoters and enhancers. A strong candidate mechanism would be shared transcriptional regulatory proteins (TRPs) that might bind regulatory regions at each locus, favouring the translocation. Objectives This project will develop and apply computational methods together with complementary laboratory experiments to identify key TRPs in normal and malignant human B-cell development.