Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells
Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells
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DOI：
10.1182/blood-2010-12-326694
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发表时间：
2011-07-14
期刊：
影响因子：
20.3
通讯作者：
Krampera, Mauro
中科院分区：
文献类型：
--
作者：
Kamdje, Armel Herve Nwabo;Mosna, Federico;Krampera, Mauro
尽管有许多关于 Notch 信号传导在 T 细胞急性淋巴细胞白血病 (ALL) 生物学中的作用的文献数据，但该分子途径在 BM 微环境中 B 系 ALL (B-ALL) 细胞发育中的重要性目前尚不清楚。在这项研究中，我们使用抗Notch分子中和抗体和γ-分泌酶抑制剂（GSI）XII来研究Notch信号通路在基质细胞支持存在下促进人B-ALL细胞存活的作用。抗Notch分子中和抗体组合治疗导致B-ALL细胞存活率下降，无论是单独培养还是与来自正常供体和B-ALL患者的基质细胞共培养。有趣的是，抑制 Notch-3 和 -4 或 Jagged-1/-2 和 DLL-1 导致 B-ALL 细胞凋亡在 3 天内急剧增加，类似于用 GSI XII 阻断所有 Notch 信号传导所获得的结果。我们的数据表明，基质细胞介导的 B-ALL 细胞抗凋亡作用是由 Notch-3 和 -4 或 Jagged-1/-2 和 DLL-1 以协同方式介导的。 (血液.2011;118(2):380-389)
Although many literature data are available on the role of Notch signaling in T-cell acute lymphoblastic leukemia (ALL) biology, the importance of this molecular pathway in the development of B-lineage ALL (B-ALL) cells in the BM microenvironment is unknown so far. In this study, we used anti-Notch molecules neutralizing Abs and gamma-secretase inhibitor (GSI) XII to investigate the role of the Notch signaling pathway in the promotion of human B-ALL cell survival in presence of stromal cell support. The treatment with combinations of anti-Notch molecule neutralizing Abs resulted in the decrease of B-ALL cell survival, either cultured alone or cocultured in presence of stromal cells from normal donors and B-ALL patients. Interestingly, the inhibition of Notch-3 and -4 or Jagged-1/-2 and DLL-1 resulted in a dramatic increase of apoptotic B-ALL cells by 3 days, similar to what is obtained by blocking all Notch signaling with the GSI XII. Our data suggest that the stromal cell-mediated antiapoptotic effect on B-ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner. (Blood.2011;118(2):380-389)