Gkotzamanidou M, Sfikakis P P, Kyrtopoulos S A, Bamia C, Dimopoulos M A, Souliotis V L
1] Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA [2] Department of Clinical Therapeutics, University of Athens School of Medicine, 11528 Athens, Greece.
First Department of Propedeutic Medicine, University of Athens School of Medicine, 11527 Athens, Greece.
Br J Cancer. 2014 Sep 23;111(7):1293-304. doi: 10.1038/bjc.2014.410. Epub 2014 Jul 22.
Melphalan is one of the most active chemotherapeutic agents in the treatment of multiple myeloma (MM). However, the mechanism underlying differential patient responses to melphalan therapy is unknown.
Chromatin structure, transcriptional activity and DNA damage response signals were examined following ex vivo treatment with melphalan of both malignant bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) of MM patients, responders (n=57) or non-responders (n=28) to melphalan therapy. PBMCs from healthy controls (n=25) were also included in the study.
In both BMPCs and PBMCs, the local chromatin looseness, transcriptional activity and repair efficiency of the transcribed strand (TS) were significantly higher in non-responders than in responders and lowest in healthy controls (all P<0.05). Moreover, we found that melphalan-induced apoptosis inversely correlated with the repair efficiency of the TS, with the duration of the inhibition of mRNA synthesis, phosphorylation of p53 at serine 15 and apoptosis rates being higher in responders than in non-responders (all P<0.001).
Our findings provide a mechanistic basis for the link between DNA repair efficiency and response to melphalan therapy. Interestingly, the observation of these phenomena in PBMCs provides a novel approach for the prediction of response to anti-myeloma therapy.
美法仑是治疗多发性骨髓瘤（MM）最有效的化疗药物之一。然而，患者对美法仑治疗反应差异的潜在机制尚不清楚。
对接受美法仑治疗的MM患者的恶性骨髓浆细胞（BMPC）和外周血单核细胞（PBMC）进行体外美法仑治疗后，检测染色质结构、转录活性和DNA损伤反应信号，其中包括对美法仑治疗有反应者（n = 57）和无反应者（n = 28）。研究还纳入了健康对照者的PBMC（n = 25）。
在BMPC和PBMC中，无反应者的局部染色质疏松度、转录活性和转录链（TS）的修复效率均显著高于有反应者，在健康对照者中最低（均P < 0.05）。此外，我们发现美法仑诱导的细胞凋亡与TS的修复效率呈负相关，有反应者的mRNA合成抑制持续时间、丝氨酸15位点的p53磷酸化水平和凋亡率均高于无反应者（均P < 0.001）。
我们的研究结果为DNA修复效率与美法仑治疗反应之间的联系提供了机制基础。有趣的是，在PBMC中观察到这些现象为预测抗骨髓瘤治疗反应提供了一种新方法。
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