UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia.
UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia.
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DOI：
10.1101/gad.276790.115
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发表时间：
2016-03-01
影响因子：
10.5
通讯作者：
Brand M
中科院分区：
文献类型：
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作者：
Benyoucef A;Palii CG;Wang C;Porter CJ;Chu A;Dai F;Tremblay V;Rakopoulos P;Singh K;Huang S;Pflumio F;Hébert J;Couture JF;Perkins TJ;Ge K;Dilworth FJ;Brand M
Benyoucef等揭示了T细胞急性淋巴细胞白血病（T-ALL）中存在亚型特异性表观遗传脆弱性，其中以致癌转录因子TAL1表达为特征的特定T-ALL亚组对组蛋白3 Lys27（H3K27）去甲基酶UTX/KDM6A的剂量和活性变化独特敏感。T细胞急性淋巴细胞白血病（T-ALL）是一组异质性血液肿瘤，由不同的亚型组成，这些亚型在遗传异常、基因表达特征和疾病方面各不相同。然而，目前尚不清楚T-ALL亚型是否在功能水平上存在差异，因此，T-ALL治疗在各亚型中的应用是一致的，导致患者之间的反应不同。在这里，我们揭示了T-ALL中存在一种亚型特异性表观遗传脆弱性，通过这种脆弱性，以致癌转录因子TAL1表达为特征的T-ALL的一个特定亚组对组蛋白3 Lys27（H3K27）去甲基化酶UTX/KDM6A的剂量和活性变化独特敏感。具体来说，我们确定UTX作为一个辅助激活剂的TAL1，并表明它作为一个主要的调节器的TAL1白血病基因表达程序。此外，我们证明，UTX，以前被描述为T-ALL的肿瘤抑制因子，实际上是一个促癌辅因子TAL1阳性（而不是TAL1阴性）的T-ALL白血病的维持。利用这种亚型特异性表观遗传脆弱性，我们提出了一种新的治疗方法，通过体内施用H3K27脱甲基酶抑制剂，有效地杀死TAL1阳性的原发性人类白血病，基于UTX抑制。这些发现首次为T-ALL患者提供了开发个性化表观遗传治疗的机会。
Benyoucef et al. reveal the existence of a subtype-specific epigenetic vulnerability in T-cell acute lymphoblastic leukemia (T-ALL) by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.