抑制赖氨酸特异性去甲基化酶1（LSD1）的药理学作用用于治疗混合系白血病重排（MLL-rearranged）白血病
Pharmacological inhibition of LSD1 for the treatment of MLL-rearranged leukemia.
作者信息
Feng Zizhen, Yao Yuan, Zhou Chao, Chen Fengju, Wu Fangrui, Wei Liping, Liu Wei, Dong Shuo, Redell Michele, Mo Qianxing, Song Yongcheng
机构信息
Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
出版信息
J Hematol Oncol. 2016 Mar 12;9:24. doi: 10.1186/s13045-016-0252-7.
BACKGROUND
Mixed lineage leukemia (MLL) gene translocations are found in ~75% infant and 10% adult acute leukemia, showing a poor prognosis. Lysine-specific demethylase 1 (LSD1) has recently been implicated to be a drug target for this subtype of leukemia. More studies using potent LSD1 inhibitors against MLL-rearranged leukemia are needed.
METHODS
LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells.
RESULTS
Potent LSD1 inhibitors with biochemical IC50 values of 9.8-77 nM were found to strongly inhibit proliferation of MLL-rearranged leukemia cells with EC50 of 10-320 nM, while these compounds are generally non-cytotoxic to several other tumor cells. LSD1 inhibition increased histone H3 lysine 4 (H3K4) methylation, downregulated expression of several leukemia-relevant genes, induced apoptosis and differentiation, and inhibited self-renewal of stem-like leukemia cells. Moreover, LSD1 inhibitors worked synergistically with inhibition of DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, against MLL-rearranged leukemia. The most potent LSD1 inhibitor showed significant in vivo activity in a systemic mouse model of MLL-rearranged leukemia without overt toxicities. Mechanistically, LSD1 inhibitors caused significant upregulation of several pathways that promote hematopoietic differentiation and apoptosis.
CONCLUSIONS
LSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.
背景
混合谱系白血病（MLL）基因易位见于约75%的婴儿和10%的成人急性白血病，预后较差。赖氨酸特异性去甲基化酶1（LSD1）最近被认为是这种白血病亚型的药物靶点。需要更多使用强效LSD1抑制剂治疗MLL重排白血病的研究。
方法
检测LSD1抑制剂对LSD1和MLL重排白血病以及其他癌细胞的生化和生物学活性。
结果
发现生化IC50值为9.8 - 77 nM的强效LSD1抑制剂能强烈抑制MLL重排白血病细胞的增殖，EC50为10 - 320 nM，而这些化合物对其他几种肿瘤细胞一般无细胞毒性。抑制LSD1可增加组蛋白H3赖氨酸4（H3K4）甲基化，下调几种白血病相关基因的表达，诱导凋亡和分化，并抑制白血病干细胞样细胞的自我更新。此外，LSD1抑制剂与组蛋白H3赖氨酸79（H3K79）甲基转移酶DOT1L的抑制剂协同作用，对抗MLL重排白血病。最有效的LSD1抑制剂在MLL重排白血病的系统性小鼠模型中显示出显著的体内活性，且无明显毒性。从机制上讲，LSD1抑制剂导致促进造血分化和凋亡的几种途径显著上调。
结论
LSD1是MLL重排白血病的药物靶点，LSD1抑制剂是该恶性肿瘤的潜在治疗药物。
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