A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression
A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression
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DOI：
10.1182/blood-2010-04-278788
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发表时间：
2011-02-24
期刊：
影响因子：
20.3
通讯作者：
Staudt, Louis M.
中科院分区：
文献类型：
--
作者：
Annunziata, Christina M.;Hernandez, Lidia;Staudt, Louis M.
调节癌基因的异常转录是癌症治疗中相对尚未探索的机会。在大约 10% 的多发性骨髓瘤中，起始致癌事件是肌肉腱膜纤维肉瘤癌基因同源物 (MAF) 的易位，MAF 是关键靶基因（包括细胞周期蛋白 D2）的转录激活因子。我们之前的研究表明，MAF 在另外 30% 的多发性骨髓瘤病例中表达上调。本研究描述了在这两种情况下诱导 MAF 转录的常见机制。 MAF 转录的第二种模式发生在多发性骨髓瘤 SET 结构域 (MMSET) 易位的骨髓瘤中。 MMSET 敲低降低了 MAF 转录和细胞活力。小分子筛选发现了一种丝裂原激活蛋白激酶激酶 (MEK) 抑制剂，可激活细胞外信号调节激酶 (ERK)MAP 激酶，减少代表 MMSET 或 MAF 亚组的细胞中的 MAF mRNA。 ERK 激活 FOS 的转录，FOS 是 AP-1 转录因子的一部分。通过染色质免疫沉淀，FOS 结合了 MAF 启动子，而 MEK 抑制则减少了这种相互作用。 MEK 抑制选择性诱导表达 MAF 的骨髓瘤细胞凋亡，而 FOS 失活也具有类似的毒性。 MAF 的重新表达使细胞免于因 MMSET 耗竭、MEK 抑制或 FOS 失活引起的死亡。本文提供的数据表明 MEK-ERK 通路调节 MAF 转录，为表达 MAF 的骨髓瘤中 MEK 抑制剂的临床评估提供分子原理。 （血。2011；117(8):2396-2404）
Modulating aberrant transcription of oncogenes is a relatively unexplored opportunity in cancer therapeutics. In approximately 10% of multiple myelomas, the initiating oncogenic event is translocation of musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a transcriptional activator of key target genes, including cyclinD2. Our prior work showed that MAF is up-regulated in an additional 30% of multiple myeloma cases. The present study describes a common mechanism inducing MAF transcription in both instances. The second mode of MAF transcription occurred in myelomas with multiple myeloma SET domain (MMSET) translocation. MMSET knockdown decreased MAF transcription and cell viability. A small-molecule screen found an inhibitor of mitogen-activated protein kinase kinase (MEK), which activates extracellular signal-regulated kinase (ERK)MAP kinases, reduced MAF mRNA in cells representing MMSET or MAF subgroups. ERK activates transcription of FOS, part of the AP-1 transcription factor. By chromatin immunoprecipitation, FOS bound the MAF promoter, and MEK inhibition decreased this interaction. MEK inhibition selectively induced apoptosis in MAF-expressing myelomas, and FOS inactivation was similarly toxic. Reexpression of MAF rescued cells from death induced by MMSET depletion, MEK inhibition, or FOS inactivation. The data presented herein demonstrate that the MEK-ERK pathway regulates MAF transcription, providing molecular rationale for clinical evaluation of MEK inhibitors in MAF-expressing myeloma. (Blood. 2011;117(8):2396-2404)