Ahmad Khalil, Scholz Bastian, Capelo Ricardo, Schweighöfer Ilona, Kahnt Astrid Stefanie, Marschalek Rolf, Steinhilber Dieter
Institute of Pharmaceutical Chemistry / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Institute of Pharmaceutical Biology / ZAFES, Goethe University Frankfurt, Frankfurt, Germany.
Oncotarget. 2015 Sep 22;6(28):25784-800. doi: 10.18632/oncotarget.4703.
The human 5-lipoxygenase (5-LO), encoded by the ALOX5 gene, is the key enzyme in the formation of pro-inflammatory leukotrienes. ALOX5 gene transcription is strongly stimulated by calcitriol (1α, 25-dihydroxyvitamin D3) and TGFβ (transforming growth factor-β). Here, we investigated the influence of MLL (activator of transcript initiation), AF4 (activator of transcriptional elongation) as well as of the leukemogenic fusion proteins MLL-AF4 (ectopic activator of transcript initiation) and AF4-MLL (ectopic activator of transcriptional elongation) on calcitriol/TGFβ-dependent 5-LO transcript elongation. We present evidence that the AF4 complex directly interacts with the vitamin D receptor (VDR) and promotes calcitriol-dependent ALOX5 transcript elongation. Activation of transcript elongation was strongly enhanced by the AF4-MLL fusion protein but was sensitive to Flavopiridol. By contrast, MLL-AF4 displayed no effect on transcriptional elongation. Furthermore, HDAC class I inhibitors inhibited the ectopic effects caused by AF4-MLL on transcriptional elongation, suggesting that HDAC class I inhibitors are potential therapeutics for the treatment of t(4;11)(q21;q23) leukemia.
由ALOX5基因编码的人类5-脂氧合酶（5-LO）是促炎性白三烯形成过程中的关键酶。维生素D3（1α,25-二羟基维生素D3）和转化生长因子-β（TGFβ）可强烈刺激ALOX5基因转录。在此，我们研究了转录起始激活因子MLL、转录延伸激活因子AF4以及致白血病融合蛋白MLL-AF4（转录起始异位激活因子）和AF4-MLL（转录延伸异位激活因子）对维生素D3/TGFβ依赖性5-LO转录延伸的影响。我们提供的证据表明，AF4复合物直接与维生素D受体（VDR）相互作用，并促进维生素D3依赖性ALOX5转录延伸。AF4-MLL融合蛋白可强烈增强转录延伸的激活作用，但对黄酮哌啶醇敏感。相比之下，MLL-AF4对转录延伸无影响。此外，I类组蛋白去乙酰化酶（HDAC）抑制剂可抑制AF4-MLL对转录延伸产生的异位效应，这表明I类HDAC抑制剂可能是治疗t(4;11)(q21;q23)白血病的潜在疗法。
