MYC是多种肿瘤的主要驱动基因，但其编码的转录因子c-Myc难以被药物靶向。已知MYC与非霍奇金淋巴瘤NHL密切相关，申请人前期研究已证实CAMKIIγ激酶与c-Myc具有协同致死关系，且该激酶通过直接磷酸化作用稳定c-Myc导致c-Myc蛋白高表达。申请人前期研究还发现在由MYC染色体易位导致c-Myc高表达的NHL中，该激酶可能通过调控c-Myc转录复合体形成和染色质重塑而增强c-Myc转录活性。基于此，本项目针对MYC染色体易位驱动的NHL，拟开展：用已构建的不同CAMKIIγ背景的小鼠与MYC染色体易位的EμMYC小鼠杂交研究该激酶在此类NHL中的作用，并进行临床相关性验证；深入研究该激酶对组蛋白H3的磷酸化作用和在染色质重塑中的功能，鉴定c-Myc转录复合体中受该激酶调控的关键蛋白。本项目将深入诠释CAMKIIγ在MYC驱动的NHL中发挥的作用，为靶向MYC的药物研发提供新思路。

The MYC oncogene is a central driver in many human cancers, including Non-Hodgkin’s lymphoma (NHL), but drug development aimed at directly targeting Myc has proved challenging. Synthetic lethality has provided a new avenue to target these “undruggable” proteins indirectly. Previous studies have identified the synthetic lethal interaction of CAMKIIγ and c-Myc overexpression. We have shown that CAMKIIγ stabilizes the c-Myc protein by directly phosphorylating c-Myc at Ser62 in NHL. Further, in NHL cells harboring MYC translocation , CAMKIIγ plays a critical role in regulating c-Myc transcriptional activity without affecting c-Myc protein, suggesting that, in addition to regulating c-Myc protein stability, CAMKIIγ might has unknown effects on c-Myc transcription activity in NHL. And our preliminary data indicated the underlying mechanisms might include the regulation of chromatin remodeling and c-Myc transcriptional complex assembly. Therefore we plan to investigate the role of CAMKIIγ in EμMyc induced NHL mice model using our unique mice strains with different CAMKIIγ status: Camk2g–/– (CAMKIIγ deleted) and Camk2gTg (CAMKIIγ constitutively activated), and further investigate the correlation of the underlying mechanisms and the clinical phenotype using NHL patients’ samples. Furthermore, we plan to study the mechanisms by which CAMKIIγ regulates c-Myc transcriptional activity in MYC-driven lymphomagenesis. Successful completion of these studies will present new opportunities for targeting this “undruggable” protein — c-Myc, and provide a novel approach for treating MYC driven lymphomas.