Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Assessment of TP53 lesions for p53 system functionality and drug resistance in multiple myeloma using an isogenic cell line model.
Scientific Reports ( IF 3.8 ) Pub Date : 2019-12-02 , DOI: 10.1038/s41598-019-54407-4 Umair Munawar 1 , Markus Roth 1 , Santiago Barrio 2 , Harald Wajant 3 , Daniela Siegmund 3 , Ralf C Bargou 1 , K Martin Kortüm 4 , Thorsten Stühmer 1
Scientific Reports ( IF 3.8 ) Pub Date : 2019-12-02 , DOI: 10.1038/s41598-019-54407-4 Umair Munawar 1 , Markus Roth 1 , Santiago Barrio 2 , Harald Wajant 3 , Daniela Siegmund 3 , Ralf C Bargou 1 , K Martin Kortüm 4 , Thorsten Stühmer 1
Affiliation
|
Recent advances in molecular diagnostics have shown that lesions affecting both copies of the gene for tumor suppressor protein 53 (TP53) count among the most powerful predictors for high-risk disease in multiple myeloma (MM). However, the functional relevance and potential therapeutic implications of single hits to TP53 remain less well understood. Here, we have for the first time approximated the different constellations of mono- and bi-allelic TP53 lesions observed in MM patients within the frame of a single MM cell line model and assessed their potential to disrupt p53 system functionality and to impart drug resistance. Both types of common first hit: point mutation with expression of mutant p53 protein or complete loss of contribution from one of two wildtype alleles strongly impaired p53 system functionality and increased resistance to melphalan. Second hits abolished remaining p53 activity and increased resistance to genotoxic drugs even further. These results fit well with the clinical drive to TP53 single- and double-hit disease in MM patients, provide a rationale for the most commonly observed double-hit constellation (del17p+ TP53 point mutation), and underscore the potential increases in MM cell malignancy associated with any type of initial TP53 lesion.
中文翻译：
使用等基因细胞系模型评估TP53病变在多发性骨髓瘤中的p53系统功能和耐药性。
分子诊断学的最新进展表明，影响肿瘤抑制蛋白53（TP53）的两个基因拷贝的病变是多发性骨髓瘤（MM）高危疾病的最有力预测因子。但是，对TP53单次点击的功能相关性和潜在的治疗意义仍知之甚少。在这里，我们首次估算了在单个MM细胞系模型框架内的MM患者中观察到的单等位基因和双等位基因TP53病变的不同星座，并评估了它们破坏p53系统功能和赋予耐药性的潜力。两种常见的首次点击：具有突变型p53蛋白的表达的点突变或两个野生型等位基因之一的完全丧失贡献，严重损害了p53系统功能并增强了对美法仑的抗性。第二次打击取消了剩余的p53活性，并进一步增强了对基因毒性药物的抵抗力。这些结果与MM患者对TP53单发和双发疾病的临床驱动非常吻合，为最常见的双发星座（del17p + TP53点突变）提供了理论依据，并强调了与MM细胞相关的恶性肿瘤的潜在增加任何类型的初始TP53病变。
更新日期：2019-12-02
中文翻译：
使用等基因细胞系模型评估TP53病变在多发性骨髓瘤中的p53系统功能和耐药性。
分子诊断学的最新进展表明，影响肿瘤抑制蛋白53（TP53）的两个基因拷贝的病变是多发性骨髓瘤（MM）高危疾病的最有力预测因子。但是，对TP53单次点击的功能相关性和潜在的治疗意义仍知之甚少。在这里，我们首次估算了在单个MM细胞系模型框架内的MM患者中观察到的单等位基因和双等位基因TP53病变的不同星座，并评估了它们破坏p53系统功能和赋予耐药性的潜力。两种常见的首次点击：具有突变型p53蛋白的表达的点突变或两个野生型等位基因之一的完全丧失贡献，严重损害了p53系统功能并增强了对美法仑的抗性。第二次打击取消了剩余的p53活性，并进一步增强了对基因毒性药物的抵抗力。这些结果与MM患者对TP53单发和双发疾病的临床驱动非常吻合，为最常见的双发星座（del17p + TP53点突变）提供了理论依据，并强调了与MM细胞相关的恶性肿瘤的潜在增加任何类型的初始TP53病变。
京公网安备 11010802027423号