GSK3-mediated MAF phosphorylation in multiple myeloma as a potential therapeutic target.
GSK3-mediated MAF phosphorylation in multiple myeloma as a potential therapeutic target.
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DOI：
10.1038/bcj.2013.67
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发表时间：
2014-01-17
影响因子：
12.8
通讯作者：
Pouponnot C
中科院分区：
文献类型：
--
作者：
Herath NI;Rocques N;Garancher A;Eychène A;Pouponnot C
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成熟抗体的血浆B细胞的增殖。多发性骨髓瘤可由起始易位引起，其中肌腱膜纤维肉瘤家族与5%的∼有关。携带MAF易位的MMS预后较差。这些易位与MAF表达升高有关，包括c-MAF、MAFB和MAFA，与t(14；16)和t(14；20)易位有关，分别涉及c-MAF和MAFB。C-MAF也通过MEK/ERK激活在MM中高表达，使MAF基因失控驱动的MMS数量接近50%。在这里，我们证明MAFB和c-MAF在人MM细胞系中被丝氨酸/苏氨酸激酶GSK3磷酸化。我们发现，LiCl诱导的GSK3抑制针对这些磷酸化，并特异性地减少表达MAF的MM细胞系的增殖和克隆形成。有趣的是，Bortezomib诱导MAF磷酸化稳定，这一观察至少可以部分解释Bortezomib对MAF易位患者的低疗效。因此，抑制GSK3可能代表了一种新的治疗方法。
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.