Spreafico Marco, Gruszka Alicja M, Valli Debora, Mazzola Mara, Deflorian Gianluca, Quintè Arianna, Totaro Maria Grazia, Battaglia Cristina, Alcalay Myriam, Marozzi Anna, Pistocchi Anna
Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
Dipartimento di Oncologia Sperimentale, Istituto Europeo di Oncologia IRCCS, Milan, Italy.
Front Cell Dev Biol. 2020 Sep 4;8:844. doi: 10.3389/fcell.2020.00844. eCollection 2020.
Histone deacetylase 8 (HDAC8), a class I HDAC that modifies non-histone proteins such as p53, is highly expressed in different hematological neoplasms including a subtype of acute myeloid leukemia (AML) bearing inversion of chromosome 16 [inv(16)]. To investigate HDAC8 contribution to hematopoietic stem cell maintenance and myeloid leukemic transformation, we generated a zebrafish model with Hdac8 overexpression and observed an increase in hematopoietic stem/progenitor cells, a phenotype that could be reverted using a specific HDAC8 inhibitor, PCI-34051 (PCI). In addition, we demonstrated that AML cell lines respond differently to PCI treatment: HDAC8 inhibition elicits cytotoxic effect with cell cycle arrest followed by apoptosis in THP-1 cells, and cytostatic effect in HL60 cells that lack p53. A combination of cytarabine, a standard anti-AML chemotherapeutic, with PCI resulted in a synergistic effect in all the cell lines tested. We, then, searched for a mechanism behind cell cycle arrest caused by HDAC8 inhibition in the absence of functional p53 and demonstrated an involvement of the canonical WNT signaling in zebrafish and in cell lines. Together, we provide the evidence for the role of HDAC8 in hematopoietic stem cell differentiation in zebrafish and AML cell lines, suggesting HDAC8 inhibition as a therapeutic target in hematological malignancies. Accordingly, we demonstrated the utility of a highly specific HDAC8 inhibition as a therapeutic strategy in combination with standard chemotherapy.
组蛋白去乙酰化酶8（HDAC8）是一种I类组蛋白去乙酰化酶，可修饰非组蛋白，如p53，在包括16号染色体倒位[inv(16)]的急性髓系白血病（AML）亚型在内的不同血液系统肿瘤中高表达。为了研究HDAC8对造血干细胞维持和髓系白血病转化的作用，我们构建了一个过表达Hdac8的斑马鱼模型，并观察到造血干/祖细胞增加，该表型可使用特异性HDAC8抑制剂PCI-34051（PCI）逆转。此外，我们证明AML细胞系对PCI治疗的反应不同：HDAC8抑制在THP-1细胞中引起细胞毒性作用，导致细胞周期停滞，随后凋亡，而在缺乏p53的HL60细胞中则产生细胞生长抑制作用。标准抗AML化疗药物阿糖胞苷与PCI联合使用在所有测试的细胞系中均产生协同作用。然后，我们寻找在缺乏功能性p53的情况下HDAC8抑制导致细胞周期停滞的机制，并证明经典WNT信号通路在斑马鱼和细胞系中发挥作用。总之，我们提供了HDAC8在斑马鱼和AML细胞系造血干细胞分化中作用的证据，表明抑制HDAC8可作为血液系统恶性肿瘤的治疗靶点。因此，我们证明了高度特异性抑制HDAC8作为联合标准化疗的治疗策略的实用性。
