Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma
Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma
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DOI：
10.1182/blood.v99.9.3398
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发表时间：
2002-05-01
期刊：
影响因子：
20.3
通讯作者：
Dörken, B
中科院分区：
文献类型：
--
作者：
Jundt, F;Anagnostopoulos, I;Dörken, B
Notch信号通过抑制某些分化步骤和诱导自我更新或向淋巴或骨髓谱系分化来控制造血祖细胞的细胞命运决定。此外，截短的Notch 1等位基因可能与10%的人T淋巴细胞白血病病例相关，当引入小鼠骨髓干细胞时，会导致T细胞肿瘤。然而，完整Notch 1的丰富表达和肿瘤发生之间的功能联系仍然缺乏。在这里，我们表明，Notch 1是高表达的B-和T-细胞来源的肿瘤细胞的霍奇金和间变性大细胞淋巴瘤。我们证明了Notch 1的致癌能力的一种新机制，通过显示肿瘤细胞上的完整Notch 1与其配体Jagged 1之间的相互作用在体外显著诱导增殖和抑制凋亡。我们进一步提供的证据表明，在霍奇金和间变性大细胞淋巴瘤中，Jagged 1在恶性和与Notch 1阳性肿瘤细胞共定位的旁观者细胞中表达。因此，Notch 1信号可能通过Jagged 1通过同型或异型细胞-细胞相互作用在肿瘤细胞中被激活，并且这些相互作用似乎有助于体内淋巴瘤的发生。因此，我们的数据表明，激活的Notch 1信号在霍奇金和间变性大细胞淋巴瘤的病理生物学中起着重要作用，它可能是一个潜在的治疗新靶点。(C)2002年，美国血液学会。
Notch signaling controls cell fate decisions of hematopoietic progenitors by Inhibiting certain steps of differentiation and Inducing either self-renewal or differentiation toward lymphoid or myeloid lineages. In addition, truncated Notch1 alleles could be associated with 10% of all cases of human T lymphoblastic leukemia and, when Introduced Into mouse bone marrow stem cells, cause T-cell neoplasms. However, functional links between the abundant expression of Intact Notch1 and oncogenesis are still lacking. Here we show that Notch1 Is highly expressed In B- and T-cell-derived tumor cells of Hodgkin and anaplastic large cell lymphoma. We demonstrate a novel mechanism for the oncogenic capacity of Notch1 by showing that the Interaction between Intact Notch1 on tumor cells and Its ligand Jagged1 dramatically induces proliferation and Inhibition of apoptosis in vitro. We further provide evidence that In Hodgkin and anaplastic large cell lymphoma, Jagged1 Is expressed In malignant and In bystander cells colocalizing with Notch1-positive tumor cells. Notch1 signaling may therefore be activated in tumor cells by Jagged1 through homotypic or heterotypic cell-cell interactions, and it seems likely that these interactions contribute to lymphomagenesis In vivo. Thus, our data suggest that activated Notch1 signaling plays an Important role in the pathobiology of Hodgkin and anaplastic large cell lymphoma and that It might be a potential new target for treatment. (C) 2002 by The American Society of Hematology.