Cocco Lucio, Finelli Carlo, Mongiorgi Sara, Clissa Cristina, Russo Domenico, Bosi Costanza, Quaranta Marilisa, Malagola Michele, Parisi Sarah, Stanzani Marta, Ramazzotti Giulia, Mariani Giulia A, Billi Anna Maria, Manzoli Lucia, Follo Matilde Y
*Cellular Signalling Laboratory, Institute of Human Anatomy, Dipartimento di Scienze Biomediche e NeuroMotorie, University of Bologna, Italy; Institute of Hematology "L. e A. Seràgnoli," S. Orsola-Malpighi University Hospital, Bologna, Italy; Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy; Unit of Blood Disease and Stem Cell Transplantation, University of Brescia, Italy; and Hematology Unit, Ospedale Civile di Piacenza, Italy.
*Cellular Signalling Laboratory, Institute of Human Anatomy, Dipartimento di Scienze Biomediche e NeuroMotorie, University of Bologna, Italy; Institute of Hematology "L. e A. Seràgnoli," S. Orsola-Malpighi University Hospital, Bologna, Italy; Hematology and Stem Cell Transplant Center, San Salvatore Hospital, Pesaro, Italy; Unit of Blood Disease and Stem Cell Transplantation, University of Brescia, Italy; and Hematology Unit, Ospedale Civile di Piacenza, Italy
J Leukoc Biol. 2015 Nov;98(5):769-80. doi: 10.1189/jlb.2MA1114-541R. Epub 2015 May 14.
This study tested the hypothesis that PI-PLCβ1 is associated with myeloid differentiation and that its expression could be useful for predicting the response of MDS patients to azacitidine, as the clinical effect of epigenetic treatments is often detectable only after several cycles of therapy. To this end, PI-PLCβ1 was quantified on 70 MDS patients (IPSS risk: 13 Low, 20 Int-1, 31 Int-2, 6 High) at baseline and during the first 3 cycles of azacitidine. Results were then compared with the hematologic response, as assessed after the sixth cycle of azacitidine therapy. Overall, 60 patients completed 6 cycles of azacitidine, and for them, a clinical and molecular evaluation was possible: 37 of these patients (62%) showed a specific increase of PI-PLCβ1 mRNA within the first 3 cycles, which was associated with a longer duration of response and with an increased myeloid differentiation, as evidenced by PI-PLCγ2 induction and the recruitment of specific myeloid-associated transcription factors to the PI-PLCβ1 promoter during azacitidine response. Moreover, the increase of cyclin D3 gene expression throughout all of the therapy showed that PI-PLCβ1-dependent signaling is indeed activated in azacitidine responder patients. Taken together, our results show that PI-PLCβ1 quantification in MDS predicts the response to azacitidine and is associated with an increased myeloid differentiation.
磷脂酰肌醇特异性磷脂酶Cβ1（PI-PLCβ1）与髓系分化相关，并且其表达对于预测骨髓增生异常综合征（MDS）患者对阿扎胞苷的反应可能有用，因为表观遗传治疗的临床效果通常仅在几个治疗周期后才能检测到。为此，在基线时以及阿扎胞苷治疗的前3个周期中，对70例MDS患者（国际预后评分系统[IPSS]风险：13例低危、20例中危-1、31例中危-2、6例高危）的PI-PLCβ1进行了定量分析。然后将结果与阿扎胞苷治疗第六周期后评估的血液学反应进行比较。总体而言，60例患者完成了6个周期的阿扎胞苷治疗，对于他们，可以进行临床和分子评估：其中37例患者（62%）在最初3个周期内PI-PLCβ1 mRNA出现特异性升高，并与更长的缓解持续时间以及髓系分化增加相关，这在阿扎胞苷反应期间通过PI-PLCγ2的诱导以及特定髓系相关转录因子募集到PI-PLCβ1启动子得以证实。此外，在整个治疗过程中细胞周期蛋白D3基因表达的增加表明，在对阿扎胞苷有反应的患者中，PI-PLCβ1依赖性信号传导确实被激活。综上所述，我们的结果表明，MDS中PI-PLCβ1的定量分析可预测对阿扎胞苷的反应，并与髓系分化增加相关。
