Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia.
Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia.
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发表时间：
2007
期刊：
影响因子：
82.9
通讯作者：
T. Vilimas;J. Mascarenhas;Teresa Palomero;M. Mandal;S. Buonamici;Fanyong Meng;B. Thompson;Christina Sp
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文献类型：
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作者：
T. Vilimas;J. Mascarenhas;Teresa Palomero;M. Mandal;S. Buonamici;Fanyong Meng;B. Thompson;Christina Sp
与其他类型的ALL不同，T细胞急性淋巴细胞白血病（T-ALL）很少与染色体畸变相关，但最近发现大多数T-ALL患者携带NOTCH 1基因的激活突变。然而，负责Notch 1诱导的肿瘤转化的信号通路和靶基因仍然不确定。我们在这里报告说，组成型激活Notch 1激活NF-κ B途径转录和通过IkappaB激酶（IKK）复合物，从而导致几个充分表征的靶基因NF-κ B在骨髓造血干细胞和祖细胞的表达增加。我们的观察结果表明，NF-κ B通路在已建立的人类T-ALL中高度活跃，并且抑制该通路可以有效地限制体外和体内肿瘤生长。这些发现确定NF-κ B是Notch 1诱导转化的主要介质之一，并表明NF-κ B通路是未来T-ALL治疗的潜在靶点。
T-cell acute lymphoblastic leukemia (T-ALL), unlike other ALL types, is only infrequently associated with chromosomal aberrations, but it was recently shown that most individuals with T-ALL carry activating mutations in the NOTCH1 gene. However, the signaling pathways and target genes responsible for Notch1-induced neoplastic transformation remain undefined. We report here that constitutively active Notch1 activates the NF-kappaB pathway transcriptionally and via the IkappaB kinase (IKK) complex, thereby causing increased expression of several well characterized target genes of NF-kappaB in bone marrow hematopoietic stem cells and progenitors. Our observations demonstrate that the NF-kappaB pathway is highly active in established human T-ALL and that inhibition of the pathway can efficiently restrict tumor growth both in vitro and in vivo. These findings identify NF-kappaB as one of the major mediators of Notch1-induced transformation and suggest that the NF-kappaB pathway is a potential target of future therapies of T-ALL.