The Potential of JAG Ligands as Therapeutic Targets and Predictive Biomarkers in Multiple Myeloma.
The Potential of JAG Ligands as Therapeutic Targets and Predictive Biomarkers in Multiple Myeloma.
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DOI：
10.3390/ijms241914558
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发表时间：
2023-09-26
影响因子：
5.6
通讯作者：
Chiaramonte R
中科院分区：
文献类型：
--
作者：
Platonova N;Lazzari E;Colombo M;Falleni M;Tosi D;Giannandrea D;Citro V;Casati L;Ronchetti D;Bolli N;Neri A;Torricelli F;Crews LA;Jamieson CHM;Chiaramonte R
缺口配体JAG1和JAG2在体外与多发性骨髓瘤(MM)细胞的增殖、耐药、自我更新以及与导致血管生成和破骨细胞生成的肿瘤微环境的病理串扰相关。这些发现提示，针对JAG配体的治疗方法可能有助于MM患者的护理，并引导我们探索JAG1和JAG2在MM活体模型和原始患者样本中的作用。JAG1和JAG2蛋白表达是MM细胞系的共同特征，因此，我们在MM异种移植模型中通过JAG1/2条件沉默来评估它们的功能。我们观察到JAG1和JAG2显示出作为MM治疗靶点的潜力，因为它们的沉默导致了肿瘤负担的减轻。此外，MM患者中JAG1和JAG2蛋白的表达与患者骨髓活检组织中MM细胞的存在呈正相关。最后，利用多发性骨髓瘤研究基金会(MMRF)Commpass全球数据集，我们表明JAG2基因表达水平是一个与患者总体生存和无进展生存相关的预测生物标志物，独立于其他主要分子或临床特征。总体而言，这些结果加强了开发JAG1/2量身定制的方法和将JAG2用作MM的预测性生物标记物的理由。
The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma (MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor microenvironment resulting in angiogenesis and osteoclastogenesis. These findings suggest that a therapeutic approach targeting JAG ligands might be helpful for the care of MM patients and lead us to explore the role of JAG1 and JAG2 in a MM in vivo model and primary patient samples. JAG1 and JAG2 protein expression represents a common feature in MM cell lines; therefore, we assessed their function through JAG1/2 conditional silencing in a MM xenograft model. We observed that JAG1 and JAG2 showed potential as therapeutic targets in MM, as their silencing resulted in a reduction in the tumor burden. Moreover, JAG1 and JAG2 protein expression in MM patients was positively correlated with the presence of MM cells in patients’ bone marrow biopsies. Finally, taking advantage of the Multiple Myeloma Research Foundation (MMRF) CoMMpass global dataset, we showed that JAG2 gene expression level was a predictive biomarker associated with patients’ overall survival and progression-free survival, independently from other main molecular or clinical features. Overall, these results strengthened the rationale for the development of a JAG1/2-tailored approach and the use of JAG2 as a predictive biomarker in MM.
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影响因子：
5.2
作者：
Palano MT;Giannandrea D;Platonova N;Gaudenzi G;Falleni M;Tosi D;Lesma E;Citro V;Colombo M;Saltarella I;Ria R;Amodio N;Taiana E;Neri A;Vitale G;Chiaramonte R
通讯作者：
Chiaramonte R
影响因子：
28.2
作者：
Briot A;Iruela-Arispe ML
通讯作者：
Iruela-Arispe ML
影响因子：
4.8
作者：
Pelullo, Maria;Quaranta, Roberta;Talora, Claudio;Checquolo, Saula;Cialfi, Samantha;Felli, Maria Pia;te Kronnie, Geertruy;Borga, Chiara;Besharat, Zein Mersini;Palermo, Rocco;Di Marcotullio, Lucia;Capobianco, Anthony J.;Gulino, Alberto;Screpanti, Isabella;Bellavia, Diana
通讯作者：
Bellavia, Diana
影响因子：
20.3
作者：
Jundt, F;Pröbsting, KS;Dörken, B
通讯作者：
Dörken, B
影响因子：
11.2
作者：
Delgado-Calle J;Anderson J;Cregor MD;Hiasa M;Chirgwin JM;Carlesso N;Yoneda T;Mohammad KS;Plotkin LI;Roodman GD;Bellido T
通讯作者：
Bellido T