Fan Fengjuan, Podar Klaus
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1277, Wuhan 430022, China.
Department of Internal Medicine II, University Hospital Krems, Mitterweg 10, 3500 Krems an der Donau, Austria.
Cancers (Basel). 2021 May 12;13(10):2326. doi: 10.3390/cancers13102326.
Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. Activator Protein-1 (AP-1) transcription factors (TFs), comprised of the JUN, FOS, ATF and MAF multigene families, are implicated in a plethora of physiologic processes and tumorigenesis including plasma cell differentiation and MM pathogenesis. Depending on the genetic background, the tumor stage, and cues of the tumor microenvironment, specific dimeric AP-1 complexes are formed. For example, AP-1 complexes containing Fra-1, Fra-2 and B-ATF play central roles in the transcriptional control of B cell development and plasma cell differentiation, while dysregulation of AP-1 family members c-Maf, c-Jun, and JunB is associated with MM cell proliferation, survival, drug resistance, bone marrow angiogenesis, and bone disease. The present review article summarizes our up-to-date knowledge on the role of AP-1 family members in plasma cell differentiation and MM pathophysiology. Moreover, it discusses novel, rationally derived approaches to therapeutically target AP-1 TFs, including protein-protein and protein-DNA binding inhibitors, epigenetic modifiers and natural products.
多发性骨髓瘤（MM）是一种无法治愈的血液系统恶性肿瘤，其特征是骨髓内恶性浆细胞的克隆性扩增。激活蛋白-1（AP-1）转录因子（TFs）由JUN、FOS、ATF和MAF多基因家族组成，参与包括浆细胞分化和MM发病机制在内的众多生理过程和肿瘤发生。根据遗传背景、肿瘤分期和肿瘤微环境的线索，会形成特定的二聚体AP-1复合物。例如，含有Fra-1、Fra-2和B-ATF的AP-1复合物在B细胞发育和浆细胞分化的转录调控中起核心作用，而AP-1家族成员c-Maf、c-Jun和JunB的失调与MM细胞增殖、存活、耐药性、骨髓血管生成和骨病有关。本综述文章总结了我们目前关于AP-1家族成员在浆细胞分化和MM病理生理学中作用的最新知识。此外，它还讨论了针对AP-1 TFs的新型合理衍生治疗方法，包括蛋白质-蛋白质和蛋白质-DNA结合抑制剂、表观遗传修饰剂和天然产物。
