Lyl1,也称为淋巴母细胞性白血病基因1,是一种基本的螺旋-环-螺旋(basic helix-loop-helix, bHLH)家族的转录因子。Lyl1在造血过程中起着关键作用,其异常表达与多种白血病的发生发展密切相关。Lyl1能够与其他转录因子结合,形成复合物,调控基因的表达,进而影响细胞的生长、分化和存活。例如,在急性髓性白血病(AML)中,Lyl1与AML1-ETO融合蛋白结合,形成AETFC复合物,调控基因表达,促进白血病的发生。Lyl1的表达水平与AML患者的预后相关,Lyl1高表达的患者预后较差[1]。此外,Lyl1在T细胞急性淋巴细胞白血病(T-ALL)中也发挥着重要作用,Lyl1的异常表达与T-ALL的发生发展密切相关[7]。
Lyl1的异常表达还与其他多种癌症的发生发展相关。例如,在子宫体子宫内膜癌(UCEC)中,Lyl1基因的扩增与患者的预后不良相关,Lyl1基因扩增的患者预后较差[2]。此外,Lyl1在前列腺癌中发挥重要作用,Lyl1的表达水平与前列腺癌患者的预后相关,Lyl1低表达的患者预后较差[5]。
Lyl1的功能不仅限于癌症的发生发展,还在免疫系统中发挥着重要作用。例如,在巨噬细胞中,Lyl1的表达受到NFκB和MAP激酶通路的调控,Lyl1的表达水平与巨噬细胞的炎症反应和细菌清除能力相关[3]。Lyl1缺陷的巨噬细胞对结核分枝杆菌的清除能力降低,炎症反应加剧,导致小鼠感染后存活率降低[3]。
Lyl1在肺动脉高压中也发挥着重要作用。在肺动脉高压患者的肺组织中,Lyl1的表达水平升高,Lyl1的异常表达与肺动脉高压的发生发展密切相关[4]。
Lyl1的功能调控机制复杂,涉及多种信号通路和转录因子。例如,在AML中,Lyl1的表达受到BRD4的调控,BRD4抑制剂GNE-987能够抑制AML细胞增殖,其机制可能与GNE-987抑制Lyl1的表达相关[6]。在前列腺癌中,Lyl1的表达受到雄激素受体(AR)的调控,过量的雄激素能够通过AR诱导Lyl1的表达,进而影响前列腺癌细胞的生长和存活[5]。
综上所述,Lyl1是一种重要的转录因子,在多种生物学过程中发挥着重要作用。Lyl1的异常表达与多种癌症的发生发展相关,Lyl1的功能调控机制复杂,涉及多种信号通路和转录因子。深入研究Lyl1的功能和调控机制,有助于我们更好地理解疾病的发病机制,为疾病的预防和治疗提供新的思路和策略。
参考文献:
1. Chen, Qian, Cevher, Murat A, Jiang, Qi, Roeder, Robert G, Chen, Mo. 2022. LYL1 facilitates AETFC assembly and gene activation by recruiting CARM1 in t(8;21) AML. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2213718119. doi:10.1073/pnas.2213718119. https://pubmed.ncbi.nlm.nih.gov/36215477/
2. Kim, Se Ik, Lee, Ji Won, Lee, Nara, Song, Yong-Sang, Seo, Jeong-Sun. 2018. LYL1 gene amplification predicts poor survival of patients with uterine corpus endometrial carcinoma: analysis of the Cancer genome atlas data. In BMC cancer, 18, 494. doi:10.1186/s12885-018-4429-z. https://pubmed.ncbi.nlm.nih.gov/29716549/
3. Jones, Shelby-Sara, Ozturk, Mumin, Kieswetter, Nathan Scott, Brombacher, Frank, Guler, Reto. 2022. Lyl1-deficiency promotes inflammatory responses and increases mycobacterial burden in response to Mycobacterium tuberculosis infection in mice. In Frontiers in immunology, 13, 948047. doi:10.3389/fimmu.2022.948047. https://pubmed.ncbi.nlm.nih.gov/36119114/
4. Saygin, Didem, Tabib, Tracy, Bittar, Humberto E T, Rojas, Mauricio, Lafyatis, Robert. 2020. Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension. In Pulmonary circulation, 10, . doi:10.1177/2045894020908782. https://pubmed.ncbi.nlm.nih.gov/32166015/
5. Heidari Horestani, Mehdi, Schindler, Katrin, Baniahmad, Aria. 2024. Functional circuits of LYL1 controlled by supraphysiological androgen in prostate cancer cells to regulate cell senescence. In Cell communication and signaling : CCS, 22, 590. doi:10.1186/s12964-024-01970-7. https://pubmed.ncbi.nlm.nih.gov/39668349/
6. Sang, Xu, Zhang, Yongping, Fang, Fang, Pan, Jian, Hu, Shaoyan. 2022. BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia. In Journal of immunology research, 2022, 7912484. doi:10.1155/2022/7912484. https://pubmed.ncbi.nlm.nih.gov/35958877/
7. Ferrando, Adolfo A, Look, A Thomas. . Gene expression profiling in T-cell acute lymphoblastic leukemia. In Seminars in hematology, 40, 274-80. doi:. https://pubmed.ncbi.nlm.nih.gov/14582078/