ALK positively regulates MYCN activity through repression of HBP1 expression
ALK positively regulates MYCN activity through repression of HBP1 expression
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DOI：
10.1038/s41388-018-0595-3
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发表时间：
2019-04-11
期刊：
影响因子：
8
通讯作者：
Speleman, Frank
中科院分区：
文献类型：
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作者：
Claeys, Shana;Denecker, Geertrui;Speleman, Frank
ALK 突变发生在 10% 的原发性神经母细胞瘤中，是精准治疗的主要靶点。与 MYCN 扩增相结合，ALK 突变推断出超高风险表型，导致患者预后非常差。为了为未来的精准用药开辟机会，更深入地了解组成型 ALK 信号传导的分子后果及其与这种侵袭性儿科肿瘤实体中 MYCN 活性的关系至关重要。我们发现突变型 ALK 通过 PI3K-AKT-FOXO3a 信号轴下调“HMG-box 转录因子 1”(HBP1)。 HBP1 抑制 MYCN 的转录激活和抑制活性，后者是通过 PRC2 活性介导的。 HBP1 本身通过与 92 类似的 miR-17 受到 MYCN 的负控制。PI3K 拮抗剂对 HBP1 的靶向作用和 BET 或 HDAC 抑制剂对 MYCN 信号的联合作用可阻断 MYCN 活性并显着减少肿瘤生长，这为高风险神经母细胞瘤提供了一种新的靶向治疗选择。
ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the 'HMG-box transcription factor 1' (HBP1) through the PI3K-AKT-FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17 similar to 92. Combined targeting of HBP1 by PI3K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.