We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their superenhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong SE at the retinoic acid receptor alpha (RARA) gene locus. The presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of acute promyelocytic leukemia treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation.Significance: We use the SE landscape of primary human AML to elucidate transcriptional circuitry and identify novel cancer vulnerabilities. A subset of patients were found to have an SE at RARA, which is predictive for response to SY-1425, a potent and selective RARα agonist, in preclinical models, forming the rationale for its clinical investigation in biomarker-selected patients. Cancer Discov; 7(10); 1136-53. ©2017 AACR.See related commentary by Wang and Aifantis, p. 1065.This article is highlighted in the In This Issue feature, p. 1047.

中文翻译：

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超级增强子分析定义了非 APL AML 的新型表观基因组亚型，包括可通过 SY-1425（一种有效的选择性 RARα 激动剂）靶向的 RARα 依赖性。

我们对 66 名急性髓系白血病 (AML) 患者的增强子景观进行了表征，确定了 6 个新的亚组及其相关的调控位点。这些亚组由其超级增强子（SE）图谱定义，与体细胞突变正交，并与不同的白血病细胞状态相关。对这些表观基因组亚型的转录驱动因素的检查发现，一部分患者的视黄酸受体 α (RARA) 基因位点具有特别强的 SE。RARA SE 的存在以及随之而来的高水平 RARA mRNA 使细胞系和离体模型对 RARα 选择性激动剂 SY-1425（他米巴罗汀）具有高度敏感性。此外，仅具有高 RARA mRNA 的 AML 患者来源的异种移植（PDX）模型被发现对 SY-1425 有反应。从机制上讲，我们发现 RARA 高 AML 细胞对 SY-1425 的反应与用类维生素A治疗的急性早幼粒细胞白血病相似，其特征是诱导已知的视黄酸反应基因、增加分化和丧失增殖。意义：我们利用人类原发性 AML 的 SE 景观来阐明转录回路并识别新的癌症脆弱性。发现一部分患者在 RARA 中出现 SE，这可以预测临床前模型中对 SY-1425（一种有效的选择性 RARα 激动剂）的反应，从而形成其在生物标志物选择的患者中进行临床研究的基本原理。癌症发现；7(10)；1136-53。©2017 AACR。参见 Wang 和 Aifantis 的相关评论，第 17 页。1065.这篇文章在本期特稿中突出显示，第 1065 页。1047.