文章：

GSK3介导的MAF磷酸化在多发性骨髓瘤中作为潜在的治疗靶点

GSK3-mediated MAF phosphorylation in multiple myeloma as a potential therapeutic target

原文发布日期：2014-01-17

DOI: 10.1038/bcj.2013.67

类型: Original Article

开放获取: 是

英文摘要：

Multiple myeloma (MM) is an incurable haematological malignancy characterised by the proliferation of mature antibody-secreting plasma B cells in the bone marrow. MM can arise from initiating translocations, of which the musculoaponeurotic fibrosarcoma (MAF) family is implicated in ∼5%. MMs bearing Maf translocations are of poor prognosis. These translocations are associated with elevated Maf expression, including c-MAF, MAFB and MAFA, and with t(14;16) and t(14;20) translocations, involving c-MAF and MAFB, respectively. c-MAF is also overexpressed in MM through MEK/ERK activation, bringing the number of MMs driven by the deregulation of a Maf gene close to 50%. Here we demonstrate that MAFB and c-MAF are phosphorylated by the Ser/Thr kinase GSK3 in human MM cell lines. We show that LiCl-induced GSK3 inhibition targets these phosphorylations and specifically decreases proliferation and colony formation of Maf-expressing MM cell lines. Interestingly, bortezomib induced stabilisation of Maf phosphorylation, an observation that could explain, at least partially, the low efficacy of bortezomib for patients carrying Maf translocations. Thus, GSK3 inhibition could represent a new therapeutic approach for these patients.

摘要翻译： 

多发性骨髓瘤（MM）是一种无法治愈的血液系统恶性肿瘤，其特征是骨髓中分泌抗体的成熟浆B细胞异常增殖。该疾病可由起始易位引发，其中肌肉腱膜纤维肉瘤（MAF）家族基因易位约占5%。携带Maf易位的多发性骨髓瘤患者预后较差。这些易位与Maf表达升高相关，包括c-MAF、MAFB和MAFA，以及分别涉及c-MAF和MAFB的t(14;16)和t(14;20)易位。通过MEK/ERK通路激活，c-MAF在多发性骨髓瘤中同样过表达，使得由Maf基因失调驱动的多发性骨髓瘤比例接近50%。本研究证明，在人多发性骨髓瘤细胞系中，MAFB和c-MAF可被Ser/Thr激酶GSK3磷酸化。我们发现LiCl诱导的GSK3抑制可靶向这些磷酸化位点，并特异性降低表达Maf的骨髓瘤细胞系的增殖和集落形成能力。值得注意的是，硼替佐米可诱导Maf磷酸化的稳定，这一观察结果至少可部分解释为何携带Maf易位的患者对硼替佐米治疗反应不佳。因此，GSK3抑制剂可能为这类患者提供新的治疗策略。

原文链接：

GSK3-mediated MAF phosphorylation in multiple myeloma as a potential therapeutic target