Boila Liberalis Debraj, Chatterjee Shankha Subhra, Banerjee Debasis, Sengupta Amitava
Stem Cell and Leukemia Laboratory, Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Translational Research Unit of Excellence (TRUE), CN 6, Sector V, Salt Lake, Kolkata 700091, West Bengal, India.
Park Clinic, Gorky Terrace, Kolkata 700017, West Bengal, India.
Exp Hematol. 2018 Feb;58:44-51.e7. doi: 10.1016/j.exphem.2017.10.002. Epub 2017 Oct 27.
Acute myeloid leukemia (AML) remains an aggressive hematopoietic malignancy that is caused by proliferation of immature myeloid cells and is frequently characterized by perturbations in chromatin-modifying enzymes. Emerging evidence indicates that histone demethylases play a role in tumorigenesis. However, due to the complexity of this enormous family of histone-modifying enzymes, substrate redundancy, and context-specific roles, the contribution of each member remains ambiguous and targeting them remains challenging. Here, we analyzed expression of histone-3-lysine (H3K) demethylases and their cognate substrates in a cohort of de novo AML patients, which demonstrated that the expression of H3K27Me3/2-demethylases and selected members of H3K9Me3/2/1-demethylases are significantly increased in AML. KDM6 upregulation is associated with a global decrease in H3K27Me3 level. Importantly, our data show that pharmacological inhibition of H3K27Me3/2-demethylases or H3K9Me3/2-demethylases, either alone or in combination, could be considered an interesting molecular therapeutic modality in human AML independent of its subtype.
急性髓系白血病（AML）仍然是一种侵袭性造血恶性肿瘤，由未成熟髓系细胞增殖引起，其特征通常是染色质修饰酶的紊乱。新出现的证据表明，组蛋白去甲基化酶在肿瘤发生中起作用。然而，由于这个庞大的组蛋白修饰酶家族的复杂性、底物冗余性以及特定背景下的作用，每个成员的贡献仍然不明确，针对它们进行靶向治疗仍然具有挑战性。在这里，我们分析了一组初发AML患者中组蛋白3赖氨酸（H3K）去甲基化酶及其同源底物的表达情况，结果表明H3K27Me3/2去甲基化酶和H3K9Me3/2/1去甲基化酶的某些成员在AML中的表达显著增加。KDM6上调与H3K27Me3水平的整体下降有关。重要的是，我们的数据表明，单独或联合对H3K27Me3/2去甲基化酶或H3K9Me3/2去甲基化酶进行药理抑制，可被视为一种针对人类AML的有趣分子治疗方式，而不考虑其亚型。
