The MYC-YBX1 Circuit in Maintaining Stem-like Vincristine-Resistant Cells in Rhabdomyosarcoma.
The MYC-YBX1 Circuit in Maintaining Stem-like Vincristine-Resistant Cells in Rhabdomyosarcoma.
复制标题
MYC-YBX1电路在横纹肌肉瘤中维持茎状抗蛋白酶耐药细胞。
作者：
横纹肌肉瘤（RMS）是一种毁灭性的小儿肉瘤。特别是，复发性疾病患者的生存结局非常差。然而，在过去的三四十年里，治疗选择没有任何重大变化，治疗失败的机制仍然知之甚少。在这项研究中，我们发现两个基因，MYC和YBX 1，对于导致耐药性的化疗耐受细胞的生存能力至关重要。我们还证明了MYC和YBX 1功能的相互调节是RMS治疗抵抗的一种新机制。靶向MYC、YBX 1及其相互作用因子是改善RMS患者生存结局的一种有前景的治疗方法。横纹肌肉瘤（RMS）是一种儿科软组织肉瘤，造成重大破坏，没有有效的治疗复发性疾病。治疗失败背后的机制知之甚少。我们的研究表明，用长春新碱处理RMS细胞导致CD 133阳性干细胞样耐药细胞增加。单细胞RNAseq分析显示，MYC和YBX 1是CD 133高表达细胞中得分最高的转录因子之一。使用CRISPR/Cas9靶向MYC和YBX 1降低了长春新碱抗性细胞的干细胞样特征和活力。MYC和YBX 1表现出相互调节，MYC与YBX 1启动子结合，YBX 1与MYC mRNA结合。MYC抑制剂MYC 361 i与长春新碱协同作用，以减少RMS斑马鱼模型中的肿瘤生长和干细胞样细胞。MYC和YBX在RMS患者中的表达呈正相关，MYC高表达与生存率低相关。靶向MYC-YBX 1轴有望改善RMS患者的生存率。
Rhabdomyosarcoma (RMS) is a devastating pediatric sarcoma. In particular, patients with relapsed disease have very poor survival outcomes. However, there has not been any significant change in therapy options for the last three or four decades, and the mechanisms underlying treatment failures remain poorly understood. In this study, we showed that two genes, MYC and YBX1, are essential for the viability of chemotherapy-tolerant cells that lead to resistance. We also demonstrated the mutual regulation of MYC and YBX1 function as a novel mechanism of therapy resistance in RMS. Targeting MYC, YBX1, and their interacting factors is a promising therapeutic approach to improve survival outcomes of RMS patients. Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma that causes significant devastation, with no effective therapy for relapsed disease. The mechanisms behind treatment failures are poorly understood. Our study showed that treatment of RMS cells with vincristine led to an increase in CD133-positive stem-like resistant cells. Single cell RNAseq analysis revealed that MYC and YBX1 were among the top-scoring transcription factors in CD133-high expressing cells. Targeting MYC and YBX1 using CRISPR/Cas9 reduced stem-like characteristics and viability of the vincristine-resistant cells. MYC and YBX1 showed mutual regulation, with MYC binding to the YBX1 promoter and YBX1 binding to MYC mRNA. The MYC inhibitor MYC361i synergized with vincristine to reduce tumor growth and stem-like cells in a zebrafish model of RMS. MYC and YBX expression showed a positive correlation in RMS patients, and high MYC expression correlated with poor survival. Targeting the MYC-YBX1 axis holds promise for improving survival in RMS patients.
登录
查看更多内容
影响因子：
64.5
作者：
Kim J;Woo AJ;Chu J;Snow JW;Fujiwara Y;Kim CG;Cantor AB;Orkin SH
通讯作者：
Orkin SH
影响因子：
64.5
作者：
Kawaguchi, Y;Kovacs, JJ;Yao, TP
通讯作者：
Yao, TP
影响因子：
8.8
作者：
Xu L;Zheng Y;Liu J;Rakheja D;Singleterry S;Laetsch TW;Shern JF;Khan J;Triche TJ;Hawkins DS;Amatruda JF;Skapek SX
通讯作者：
Skapek SX
影响因子：
13.6
作者：
Danielli, Sara G.;Porpiglia, Ermelinda;De Micheli, Andrea J.;Navarro, Natalia;Zellinger, Michael J.;Bechtold, Ingrid;Kisele, Samanta;Volken, Larissa;Marques, Joana G.;Kasper, Stephanie;Bode, Peter K.;Henssen, Anton G.;Guergen, Dennis;Delattre, Olivier;Surdez, Didier;Roma, Josep;Buhlmann, Peter;Blau, Helen M.;Wachtel, Marco;Schafer, Beat W.
通讯作者：
Schafer, Beat W.
影响因子：
50.3
作者：
Ignatius, Myron S.;Chen, Eleanor;Langenau, David M.
通讯作者：
Langenau, David M.