Yao Jingfang, Li Gentao, Cui Zihui, Chen Peilei, Wang Jinhong, Hu Zhenbo, Zhang Lei, Wei Liuya
Laboratory for Stem Cell and Regenerative Medicine, Affiliated Hospital of Weifang Medical University, Weifang, China.
School of Pharmacy, Weifang Medical University, Weifang, China.
Front Pharmacol. 2022 Apr 27;13:876076. doi: 10.3389/fphar.2022.876076. eCollection 2022.
Acute leukemia (AL) is characterized by excessive proliferation and impaired differentiation of leukemic cells. AL includes acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Previous studies have demonstrated that about 10% of AML and 22% of ALL are mixed lineage leukemia gene rearrangements (MLLr) leukemia. The prognosis of MLLr leukemia is poor and new therapeutics are urgently needed. Differentiation therapy with all-trans-retinoic acid (ATRA) has prolonged the 5-years disease-free survival rate in acute promyelocytic leukemia (APL), a subtype of AML. However, the differentiation therapy has not been effective in other acute leukemia. Here, we aim to explore the cell differentiation effect of the potent HDACs inhibitor, I1, and the possible mechanism on the MLLr-AML and MLLr-ALL cells (MOLM-13, THP-1, MV4-11 and SEM). It is shown that I1 can significantly inhibit the proliferation and the colony-forming ability of MOLM-13, THP-1, MV4-11 and SEM cells by promoting cell differentiation coupled with cell cycle block at G0/G1 phase. We show that the anti-proliferative effect of I1 attributed to cell differentiation is most likely associated with the HDAC inhibition activity, as assessed by the acetylation of histone H3 and H4, which may dictates the activation of hematopoietic cell lineage pathway in both MOLM-13 and THP-1 cell lines. Moreover, the activity of HDAC inhibition of I1 is stronger than that of SAHA in MOLM-13 and THP-1 cells. Our findings suggest that I1, as a chromatin-remodeling agent, could be a potent epigenetic drug to overcome differentiation block in MLLr-AL patients and would be promising for the treatment of AL.
急性白血病（AL）的特征是白血病细胞过度增殖和分化受损。AL包括急性髓系白血病（AML）和急性淋巴细胞白血病（ALL）。先前的研究表明，约10%的AML和22%的ALL是混合谱系白血病基因重排（MLLr）白血病。MLLr白血病的预后较差，迫切需要新的治疗方法。全反式维甲酸（ATRA）的分化疗法延长了急性早幼粒细胞白血病（APL，AML的一种亚型）的5年无病生存率。然而，分化疗法在其他急性白血病中并未有效。在此，我们旨在探索强效组蛋白去乙酰化酶（HDACs）抑制剂I1对MLLr-AML和MLLr-ALL细胞（MOLM-13、THP-1、MV4-11和SEM）的细胞分化作用及其可能机制。结果表明，I1可通过促进细胞分化并使细胞周期阻滞在G0/G1期，显著抑制MOLM-13、THP-1、MV4-11和SEM细胞的增殖及集落形成能力。我们发现，I1通过细胞分化产生的抗增殖作用很可能与HDAC抑制活性有关，通过组蛋白H3和H4的乙酰化评估，这可能决定了MOLM-13和THP-1细胞系中造血细胞谱系途径的激活。此外，在MOLM-13和THP-1细胞中，I1的HDAC抑制活性强于SAHA。我们的研究结果表明，I1作为一种染色质重塑剂，可能是一种有效的表观遗传药物，可克服MLLr-AL患者的分化阻滞，有望用于治疗AL。
