文章：

MLL重排的AML细胞对全反式维甲酸的敏感性与RARα启动子区域H3K4me2的水平有关

Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is associated with the level of H3K4me2 in the RARα promoter region

原文发布日期：2014-04-25

DOI: 10.1038/bcj.2014.25

类型: Original Article

开放获取: 是

英文摘要：

All-trans retinoic acid (ATRA) is well established as differentiation therapy for acute promyelocytic leukemia (APL) in which the PML–RARα (promyelocytic leukemia-retinoic acid receptor α) fusion protein causes blockade of the retinoic acid (RA) pathway; however, in types of acute myeloid leukemia (AML) other than APL, the mechanism of RA pathway inactivation is not fully understood. This study revealed the potential mechanism of high ATRA sensitivity of mixed-lineage leukemia (MLL)-AF9-positive AML compared with MLL-AF4/5q31-positive AML. Treatment with ATRA induced significant myeloid differentiation accompanied by upregulation of RARα, C/EBPα, C/EBPɛ and PU.1 in MLL-AF9-positive but not in MLL-AF4/5q31-positive cells. Combining ATRA with cytarabine had a synergistic antileukemic effect in MLL-AF9-positive cells in vitro. The level of dimethyl histone H3 lysine 4 (H3K4me2) in the RARα gene-promoter region, PU.1 upstream regulatory region (URE) and RUNX1+24/+25 intronic enhancer was higher in MLL-AF9-positive cells than in MLL-AF4-positive cells, and inhibiting lysine-specific demethylase 1, which acts as a histone demethylase inhibitor, reactivated ATRA sensitivity in MLL-AF4-positive cells. These findings suggest that the level of H3K4me2 in the RARα gene-promoter region, PU.1 URE and RUNX1 intronic enhancer is determined by the MLL-fusion partner. Our findings provide insight into the mechanisms of ATRA sensitivity in AML and novel treatment strategies for ATRA-resistant AML.

摘要翻译： 

全反式维甲酸（ATRA）作为急性早幼粒细胞白血病（APL）的分化疗法已得到广泛认可，其中PML-RARα（早幼粒细胞白血病-维甲酸受体α）融合蛋白会导致维甲酸（RA）通路受阻；然而，在APL以外的其他类型急性髓系白血病（AML）中，RA通路失活的机制尚未完全明确。本研究揭示了MLL-AF9阳性AML相较于MLL-AF4/5q31阳性AML具有高ATRA敏感性的潜在机制。ATRA处理能诱导MLL-AF9阳性细胞发生显著的髓系分化，并伴随RARα、C/EBPα、C/EBPε和PU.1的上调，但在MLL-AF4/5q31阳性细胞中无此效应。体外实验中，ATRA与阿糖胞苷联用对MLL-AF9阳性细胞具有协同抗白血病作用。MLL-AF9阳性细胞中RARα基因启动子区、PU.1上游调控区（URE）及RUNX1+24/+25内含子增强子区域的组蛋白H3赖氨酸4二甲基化（H3K4me2）水平高于MLL-AF4阳性细胞，而抑制赖氨酸特异性去甲基化1（作为组蛋白去甲基化抑制剂）可重新激活MLL-AF4阳性细胞对ATRA的敏感性。这些发现表明，RARα基因启动子区、PU.1 URE和RUNX1内含子增强子区域的H3K4me2水平由MLL融合伴侣决定。我们的研究为理解AML中ATRA敏感性的机制及针对ATRA耐药AML的新治疗策略提供了重要见解。

原文链接：

Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is associated with the level of H3K4me2 in the RARα promoter region