Feng Zizhen, Yao Yuan, Zhou Chao, Chen Fengju, Wu Fangrui, Wei Liping, Liu Wei, Dong Shuo, Redell Michele, Mo Qianxing, Song Yongcheng
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.
J Hematol Oncol. 2016 Mar 12;9:24. doi: 10.1186/s13045-016-0252-7.
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.
LSD1 inhibitors were examined for their biochemical and biological activities against LSD1 and MLL-rearranged leukemia as well as other cancer cells.
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.
LSD1 is a drug target for MLL-rearranged leukemia, and LSD1 inhibitors are potential therapeutics for the malignancy.
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。
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。
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。
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。
