Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia.
Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia.
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急性早幼粒细胞白血病(APL)是急性髓系白血病(AML)的一种细胞遗传学亚型，以t(15；17)相关的PML-RARA融合为特征，已成功地用全反式维甲酸(ATRA)来区分白血病原始细胞。然而，在非APL AML患者中，基于ATRA的治疗并不有效。在这里，我们表明，通过表观遗传重新编程，赖氨酸特异性去甲基酶1(LSD1，也称为KDM1A)的抑制剂，包括三羟环丙胺(TCP)，解锁了非APL AML中ATRA驱动的治疗反应。抑制LSD1不会导致整个基因组中组蛋白3-Lys4二甲基化(H3K4me2)的大规模增加，但它确实增加了H3K4me2和髓系分化相关基因的表达。值得注意的是，ATRA联合TCP治疗显著减少了原代人类AML细胞在非肥胖糖尿病(NOD)-严重联合免疫缺陷(SCID)小鼠体内的植入，这表明ATRA联合TCP可能针对白血病启动细胞。此外，人急性髓系白血病细胞在NOD-SCIDγ(白细胞介素2受体γ链缺失)小鼠体内移植15d后开始全反式维甲酸和三氯苯酚联合治疗，也表明全反式维甲酸和三氯苯丙酸联合治疗具有强大的抗白血病作用，优于单独使用任何一种药物。这些数据表明LSD1是一个治疗靶点，并强烈提示它可能通过抑制ATRA的正常促分化功能而参与AML的发病，为AML的新联合治疗铺平了道路。
Acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML), characterized by the t(15;17)-associated PML-RARA fusion, has been successfully treated with therapy utilizing all-trans-retinoic acid (ATRA) to differentiate leukemic blasts. However, among patients with non- APL AML, ATRA-based treatment has not been effective. Here we show that, through epigenetic reprogramming, inhibitors of lysine- specific demethylase 1 (LSD1, also called KDM1A), including tranylcypromine (TCP), unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to a large-scale increase in histone 3 Lys4 dimethylation (H3K4me2) across the genome, but it did increase H3K4me2 and expression of myeloid-differentiation–associated genes. Notably, treatment with ATRA plus TCP markedly diminished the engraftment of primary human AML cells in vivo in nonobese diabetic (NOD)- severe combined immunodeficient (SCID) mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP treatment 15 d after engraftment of human AML cells in NOD-SCID γ (with interleukin-2 (IL-2) receptor γ chain deficiency) mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect that was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for new combinatorial therapies for AML.
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影响因子：
20.3
作者：
McDermott, Sean P.;Eppert, Kolja;Dick, John E.
通讯作者：
Dick, John E.
小分子和组蛋白底物类似物作为LSD1赖氨酸脱甲基酶抑制剂的比较分析。
影响因子：
15
作者：
Culhane, Jeffrey C.;Wang, Dongqing;Yen, Paul M.;Cole, Philip A.
通讯作者：
Cole, Philip A.
影响因子：
6.4
作者：
Hayami, Shinya;Kelly, John D.;Hamamoto, Ryuji
通讯作者：
Hamamoto, Ryuji
影响因子：
3.2
作者：
Petrie, Kevin;Zelent, Arthur;Waxman, Samuel
通讯作者：
Waxman, Samuel
影响因子：
15
作者：
Binda, Claudia;Valente, Sergio;Mai, Antonello
通讯作者：
Mai, Antonello