Cancer Research UK Leukaemia Biology Laboratory, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
Cancer Cell. 2012 Apr 17;21(4):473-87. doi: 10.1016/j.ccr.2012.03.014. Epub 2012 Mar 29.
Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogs active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia, which may be selectively targeted to therapeutic effect.
利用人源 MLL-AF9 白血病的小鼠模型，我们发现赖氨酸特异性去甲基酶 KDM1A（LSD1 或 AOF2）是白血病干细胞（LSC）潜能的关键调节因子。KDM1A 在基因组上与 MLL-AF9 结合的位置发挥作用，维持相关致癌程序的表达，从而阻止分化和凋亡。在体外和体内，使用在纳摩尔范围内有效的曲奈普汀类似物靶向 KDM1A，可模拟在具有 MLL 易位的鼠源和原发性人 AML 细胞中敲低 Kdm1a 的表型。相比之下，正常造血干细胞和祖细胞的集落形成和再群体能力未受影响。我们的数据确立了 KDM1A 作为 MLL 白血病分化阻滞的关键效应因子，它可能被选择性地靶向治疗效果。
