Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.
Blood. 2011 Jul 14;118(2):380-9. doi: 10.1182/blood-2010-12-326694. Epub 2011 May 20.
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 γ-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.
尽管有许多文献资料表明 Notch 信号通路在 T 细胞急性淋巴细胞白血病（ALL）生物学中的作用，但迄今为止，该分子途径在骨髓微环境中 B 细胞系 ALL（B-ALL）细胞发育中的重要性尚不清楚。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 信号通路在促进人类 B-ALL 细胞在基质细胞支持下存活中的作用。单独培养或与来自正常供体和 B-ALL 患者的基质细胞共培养时，用抗 Notch 分子中和抗体的组合处理会导致 B-ALL 细胞存活减少。有趣的是，抑制 Notch-3 和 -4 或 Jagged-1/-2 和 DLL-1 会导致凋亡的 B-ALL 细胞在 3 天内急剧增加，这与用 GSI XII 阻断所有 Notch 信号通路所获得的结果相似。我们的数据表明，基质细胞对 B-ALL 细胞的抗凋亡作用是通过 Notch-3 和 -4 或 Jagged-1/-2 和 DLL-1 以协同方式介导的。
