Nefedova Yulia, Cheng Pingyan, Alsina Melissa, Dalton William S, Gabrilovich Dmitry I
H Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA.
Blood. 2004 May 1;103(9):3503-10. doi: 10.1182/blood-2003-07-2340. Epub 2003 Dec 11.
The bone marrow (BM) microenvironment plays a critical role in malignant cell growth, patient survival, and response to chemotherapy in hematologic malignancies. However, mechanisms associated with this environmental influence remain unclear. In this study, we investigated the role of Notch family proteins in myeloma and other malignant lymphoid cell line growth and response to chemotherapeutic drugs. All 8 tested cell lines expressed Notch-3 and Notch-4; 7 cell lines expressed Notch-1; and 6 expressed Notch-2 proteins. Interaction with BM stroma (BMS) activated Notch signaling in tumor cells. However, activation of only Notch-1, but not Notch-2, resulted in protection of tumor cells from melphalan- and mitoxantrone-induced apoptosis. This protection was associated with up-regulation of p21(WAF/Cip) and growth inhibition of cells. Overexpression of Notch-1 in Notch-1(-) U266 myeloma cells up-regulated p21 and resulted in protection from drug-induced apoptosis. Thus, this is a first report demonstrating that Notch-1 signaling may be a primary mechanism mediating the BMS influence on hematologic malignant cell growth and survival.
骨髓（BM）微环境在血液系统恶性肿瘤的恶性细胞生长、患者生存及化疗反应中起关键作用。然而，与这种环境影响相关的机制仍不清楚。在本研究中，我们调查了Notch家族蛋白在骨髓瘤及其他恶性淋巴细胞系生长和对化疗药物反应中的作用。所有8种受试细胞系均表达Notch-3和Notch-4；7种细胞系表达Notch-1；6种表达Notch-2蛋白。与骨髓基质（BMS）相互作用可激活肿瘤细胞中的Notch信号。然而，仅Notch-1的激活而非Notch-2的激活可使肿瘤细胞免受美法仑和米托蒽醌诱导的凋亡。这种保护作用与p21（WAF/Cip）的上调及细胞生长抑制相关。在Notch-1（-）U266骨髓瘤细胞中Notch-1的过表达上调了p21并使其免受药物诱导的凋亡。因此，这是首次报道表明Notch-1信号可能是介导BMS对血液系统恶性细胞生长和生存影响的主要机制。
