Gravina Teresa, Boggio Chiara Maria Teresa, Gorla Elisa, Racca Luisa, Polidoro Silvia, Centonze Sara, Ferrante Daniela, Lunghi Monia, Graziani Andrea, Corà Davide, Baldanzi Gianluca
Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy.
Center for Translational Research on Allergic and Autoimmune Diseases (CAAD), University of Piemonte Orientale, 28100 Novara, Italy.
Biomedicines. 2023 Jul 1;11(7):1877. doi: 10.3390/biomedicines11071877.
Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including , and , without a precise correlation with specific AML subtypes. In the TGCA database, high expression negatively correlates with survival, while high expression is associated with a more favorable prognosis. and also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high expression is correlated with shorter survival. To assess the suitability of DGKs as therapeutic targets, we treated HL-60 and HEL cells with DGK inhibitors and compared cell growth and survival with those of untransformed lymphocytes. We observed a specific sensitivity to R59022 and R59949, two poorly selective inhibitors, which promoted cytotoxicity and cell accumulation in the S phase in both cell lines. Conversely, the DGKA-specific inhibitors CU-3 and AMB639752 showed poor efficacy. These findings underscore the pivotal and isoform-specific involvement of DGKs in AML, offering a promising pathway for the identification of potential therapeutic targets. Notably, the and isoforms emerge as relevant players in AML pathogenesis, albeit DGKA inhibition alone seems insufficient to impair AML cell viability.
二酰基甘油激酶（DGKs）在细胞转化和免疫监视中发挥双重作用。根据癌症表达数据库，急性髓系白血病（AML）表现出多种DGK亚型的显著过表达，包括[具体亚型1]、[具体亚型2]和[具体亚型3]，与特定的AML亚型没有精确的相关性。在TGCA数据库中，高[亚型1]表达与生存率呈负相关，而高[亚型2]表达与更有利的预后相关。[亚型1]和[亚型2]还具有不同的共表达基因模式。相反，BeatAML和TARGET数据库显示，高[亚型3]表达与较短的生存期相关。为了评估DGKs作为治疗靶点的适用性，我们用DGK抑制剂处理HL-60和HEL细胞，并将细胞生长和存活率与未转化的淋巴细胞进行比较。我们观察到对R59022和R59949这两种选择性较差的抑制剂具有特异性敏感性，这两种抑制剂在两种细胞系中均促进了细胞毒性和S期细胞积累。相反，DGKA特异性抑制剂CU-3和AMB639752显示出较差的疗效。这些发现强调了DGKs在AML中的关键作用和亚型特异性参与，为确定潜在治疗靶点提供了一条有前景的途径。值得注意的是，[亚型1]和[亚型2]亚型在AML发病机制中成为相关参与者，尽管单独抑制DGKA似乎不足以损害AML细胞活力。
