FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.
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DOI：
10.1084/jem.20070876
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发表时间：
2007-08-06
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影响因子：
--
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作者：
O'Neil J;Grim J;Strack P;Rao S;Tibbitts D;Winter C;Hardwick J;Welcker M;Meijerink JP;Pieters R;Draetta G;Sears R;Clurman BE;Look AT
γ-分泌酶抑制剂（GSI）可以在体外阻断NOTCH受体信号传导，因此为依赖于失调的NOTCH活性的肿瘤提供有吸引力的靶向治疗。为了阐明T细胞急性淋巴细胞白血病（T-ALL）中GSI耐药的基础，我们研究了具有NOTCH胞内结构域（NICD）组成性表达但缺乏NOTCH 1 C末端截短突变的T-ALL细胞系。检查的7个细胞系中的每一个和81个原发性T-ALL样本中的7个（8.6%）携带基因FBW 7的突变或纯合缺失，FBW 7是一种与NICD周转有关的泛素连接酶。事实上，我们发现FBW 7突变体不能结合NICD，并定义了FBW 7结合所需的NICD的磷酸降解决定子区域。虽然FBW 7的突变形式仍然能够结合MYC，但它们不靶向它进行降解，这表明NICD及其主要下游靶标MYC的稳定可能有助于FBW 7突变白血病的转化。此外，我们发现所有7个具有FBW 7突变的白血病细胞系对MRK-003 GSI具有耐药性。在用MRK-003处理后，这些抗性系中的大多数也未能下调NOTCH靶MYC和DELTEX 1的mRNA水平，这意味着具有FBW 7突变的T-ALL中的残留NOTCH信号传导有助于GSI抗性。
γ-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance.
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影响因子：
10.5
作者：
Clurman, BE;Sheaff, RJ;Roberts, JM
通讯作者：
Roberts, JM
影响因子：
16
作者：
Hao, Bing;Oehlmann, Stephanie;Pavletich, Nikola P.
通讯作者：
Pavletich, Nikola P.
DOI：
10.1073/pnas.0603371103
发表时间：
2006-06-13
影响因子：
11.1
作者：
Klinakis, Apostolos;Szaboics, Matthias;Efstratiadis, Argiris
通讯作者：
Efstratiadis, Argiris
影响因子：
64.8
作者：
JARRIAULT, S;BROU, C;ISRAEL, A
通讯作者：
ISRAEL, A
影响因子：
20.3
作者：
Lin, YW;Nichols, RA;Aplan, PD
通讯作者：
Aplan, PD