染色体大片段缺失是血液肿瘤的特征之一，且与患者预后不良密切相关。我们最新的研究利用基因工程小鼠模型证明染色体17p缺失能促进淋巴瘤和白血病的发生（Liu et al., Nature 2016）。通过高通量shRNA文库筛选我们进一步鉴定了染色体17p中p53之外的多个新的肿瘤抑制基因。其中花生四烯酸脱氧酶ALOX15B、ALOX12B和ALOXE3在17p上串联形成一个基因簇。我们计划利用RNA干扰、CRISPR/Cas9基因组编辑、模式动物等研究这些ALOX基因以及这一基因簇作为一个整体在Eμ-MYC诱导的淋巴瘤发生发展中的作用。初步结果显示ALOX的代谢底物花生四烯酸可能是ALOX基因抑制肿瘤的重要介质。我们将进一步阐述ALOX缺失引起的代谢异常调控淋巴瘤的分子机制。我们的研究将有助于深入理解染色体缺失及其相关的肿瘤代谢在血液肿瘤发生发展中意义。

Chromosome large deletions are one of the hallmarks of hematopoietic malignancies and associated with poor prognosis. With genetic engineered mouse models, our recent studies demonstrated that chromosome 17p deletions associated with p53 loss of heterozygosity could promote lymphoma and leukemia genesis through p53 independent mechanisms (Liu et al., Nature 2016). Through high throughput shRNA library screenings, we further identified multiple novel tumor suppressors on 17p. Among them there are three arachidonate lipoxygenases, ALOX15B, ALOX12B and ALOXE3, which align as a gene cluster. We are going to study the functions of these individual ALOX genes and this gene cluster as a whole in Eμ-MYC driven lymphoma by RNAi, CRISPR/Cas9 genome editing and animal models. Our primary results suggest that arachidonic acid, the substrate of ALOX genes, might be a critical mediator for ALOX tumor suppression function. We will further investigate the detailed molecular mechanisms of ALOX loss-induced metabolism abnormalities in lymphoma. Our studies would shed light on the deep understanding of chromosome large deletions and associated cancer metabolisms in blood cancers.