Abstract:
Bone marrow stromal cells (BMSCs) can promote the growth of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Histone deacetylases (HDACs) play essential roles in the proliferation and apoptosis resistance of Ph + ALL cells. In our previous study, inhibiting histone deacetylase 1 (HDAC1) decreases the proliferation of Ph + ALL cells. However, little is known regarding how HDAC1 in BMSCs of Ph + ALL patients affects the imatinib (IM) resistance. Therefore, the present work examined the roles of HDAC1 in BMSCs. Overexpression of HDAC1 was found in BMSCs of Ph + ALL patients with IM resistance. In addition, the Ph + ALL cell line SUP-B15 was co-cultured with BMSCs after lentivirus transfection for regulating HDAC1 expression. Knockdown of HDAC1 within BMSCs elevated the IM-mediated SUP-B15 cell apoptosis, while increasing HDAC1 expression had an opposite effect. IL-6 in BMSCs, which is an important factor for the microenvironment-associated chemoresistance, showed evident up-regulation in HDAC1-upregulated BMSCs and down-regulation in HDAC1-downregulated BMSCs. While recombinant IL-6 (rIL-6) can reversed the sensitivity of SUP-B15 cells to IM induced by downregulating HDAC1 expression in BMSCs. HDAC1 showed positive regulation on IL-6 transcription and secretion. Moreover, IL-6 secretion induced by HDAC1 in BMSCs might enhance IM resistance in Ph + ALL cells. With regard to the underlying molecular mechanism, NF-κB, an important signal responsible for IL-6 transcription in BMSCs, mediated the HDAC1-regulated IL-6 expression. Collectively, this study facilitated to develop HDAC1 inhibitors based not only the corresponding direct anti-Ph + ALL activity but also the regulation of bone marrow microenvironment.
摘要:
骨髓基质细胞(BMSCs)可促进费城染色体阳性(Ph+)急性淋巴细胞白血病(ALL)的生长。组蛋白去乙酰化酶(HDACs)在Ph+ALL细胞的增殖和抗凋亡中发挥重要作用。在我们之前的研究中,抑制组蛋白脱乙酰酶1(HDAC1)降低PhALL细胞的增殖。然而,关于Ph+ALL患者BMSCs中的HDAC1如何影响伊马替尼(IM)耐药,人们知之甚少.因此,本工作研究了HDAC1在BMSCs中的作用。在IM耐药的PhALL患者的BMSCs中发现HDAC1过表达。此外,慢病毒转染后,PhALL细胞系SUP-B15与BMSCs共培养,以调节HDAC1的表达。BMSCs中HDAC1的敲除提高IM介导的SUP-B15细胞凋亡,而增加HDAC1表达则有相反的作用。BMSCs中的IL-6,这是微环境相关化学抗性的重要因素,在HDAC1上调的BMSCs中显示出明显的上调,在HDAC1下调的BMSCs中显示出明显的下调。而重组IL-6(rIL-6)可以通过下调BMSCs中HDAC1的表达来逆转SUP-B15细胞对IM诱导的敏感性。HDAC1对IL-6的转录和分泌表现出正向调节。此外,HDAC1诱导BMSCs分泌IL-6可能增强Ph+ALL细胞IM抗性。关于潜在的分子机制,NF-κB,在BMSCs中负责IL-6转录的重要信号,介导HDAC1调节的IL-6表达。总的来说,这项研究不仅基于相应的直接抗PhALL活性,而且还基于骨髓微环境的调节,促进了HDAC1抑制剂的开发。