Follo Matilde Y, Finelli Carlo, Mongiorgi Sara, Clissa Cristina, Bosi Costanza, Testoni Nicoletta, Chiarini Francesca, Ramazzotti Giulia, Baccarani Michele, Martelli Alberto M, Manzoli Lucia, Martinelli Giovanni, Cocco Lucio
Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, Via Irnerio 48, Bologna, Italy.
Proc Natl Acad Sci U S A. 2009 Sep 29;106(39):16811-6. doi: 10.1073/pnas.0907109106. Epub 2009 Sep 10.
Lipid signaling pathways are involved in cell growth, differentiation, and apoptosis, and could have a role in the progression of myelodysplastic syndromes (MDS) into acute myeloid leukemia (AML). Indeed, recent studies showed that phosphoinositide-phospholipase (PI-PL)Cbeta1 mono-allelic deletion correlates with a higher risk of AML evolution. Also, a single patient treated with azacitidine, a DNA methyltransferase inhibitor currently used in MDS, displayed a direct correlation between PI-PLCbeta1 gene expression and drug responsiveness. Consequently, we hypothesized that PI-PLCbeta1 could be a target for demethylating therapy. First, we analyzed the structure of PI-PLCbeta1 gene promoter, then quantified the degree of PI-PLCbeta1 promoter methylation and gene expression in MDS patients at baseline and during azacitidine administration. Indeed, PI-PLCbeta1 mRNA increased in responder patients, along with a reduction of PI-PLCbeta1 promoter methylation. Also, the molecular response correlated to and anticipated the clinical outcome, thus suggesting that PI-PLCbeta1 gene reactivation could predict azacitidine responsiveness. Our results demonstrate not only that PI-PLCbeta1 promoter is hypermethylated in high-risk MDS patients, but also that the amount of PI-PLCbeta1 mRNA could predict the clinical response to azacitidine, therefore indicating a promising new therapeutic approach.
脂质信号通路参与细胞生长、分化和凋亡，可能在骨髓增生异常综合征（MDS）进展为急性髓系白血病（AML）过程中发挥作用。事实上，最近的研究表明，磷酸肌醇 - 磷脂酶（PI - PL）Cβ1单等位基因缺失与AML进展的较高风险相关。此外，一名接受阿扎胞苷治疗的患者（阿扎胞苷是目前用于MDS治疗的一种DNA甲基转移酶抑制剂）显示，PI - PLCβ1基因表达与药物反应性之间存在直接关联。因此，我们推测PI - PLCβ1可能是去甲基化治疗的一个靶点。首先，我们分析了PI - PLCβ1基因启动子的结构，然后对MDS患者基线期及阿扎胞苷给药期间PI - PLCβ1启动子甲基化程度和基因表达进行了定量分析。的确，在有反应的患者中，PI - PLCβ1 mRNA增加，同时PI - PLCβ1启动子甲基化减少。此外，分子反应与临床结果相关且可预测临床结果，这表明PI - PLCβ1基因再激活可预测阿扎胞苷的反应性。我们的结果不仅表明高危MDS患者中PI - PLCβ1启动子高度甲基化，而且PI - PLCβ1 mRNA的量可预测对阿扎胞苷的临床反应，因此提示了一种有前景的新治疗方法。
