Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China.
State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200240, Shanghai, China.
Oncogene. 2020 Sep;39(36):5888-5901. doi: 10.1038/s41388-020-01408-7. Epub 2020 Jul 30.
MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.
MLL 经历多种不同的染色体易位，导致预后不良的侵袭性白血病。除了在白血病发生中的既定作用外，MLL 融合还具有潜在的肿瘤抑制活性，可以通过药理学手段（如蛋白酶体抑制剂（PIs））来利用这种活性作为有效的癌症治疗策略。在这里，我们使用 MLL 重排的异种移植物和 MLL 白血病细胞作为模型，表明野生型 MLL 对于 MLL 融合的潜在肿瘤抑制活性是必不可少的。MLL 功能障碍，表现为 MLL 的染色质积累和随后的降解丧失，损害了 MLL-AF4 的潜在肿瘤抑制作用，并有助于获得对 PI 的耐药性。从机制上讲，MLL 功能障碍是由慢性 PI 治疗诱导的表观遗传重编程引起的，通过 H2Bub-ASH2L-MLL 轴，并且可以通过组蛋白去乙酰化酶（HDAC）抑制剂特异性恢复，组蛋白去乙酰化酶诱导组蛋白乙酰化并募集 MLL 到染色质上，以促进细胞周期基因表达。我们的发现不仅证明了 MLL 白血病细胞中不可避免地获得 PI 耐药性的机制，而且还表明，防止出现 PI 耐药细胞是与 PI 和 HDAC 抑制剂联合治疗 MLL 白血病的新策略。
