Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia
Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia
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DOI：
10.1172/jci35090
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发表时间：
2008-09-01
影响因子：
15.9
通讯作者：
Pear, Warren S.
中科院分区：
文献类型：
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作者：
Chiang, Mark Y.;Xu, Lanwei;Pear, Warren S.
在50%-70%的人类T细胞急性淋巴细胞白血病/淋巴瘤(T-ALL)病例中发现了功能获得NOTCH1突变。启动强下游信号的功能获得NOTCH1等位基因会在小鼠中引发白血病，但尚不清楚在T-ALL患者中最常见的功能获得NOTCH1突变是否会产生足够强的下游信号来诱发白血病。我们通过在小鼠造血祖细胞中表达不同强度的人类功能获得性NOTCH1等位基因来解决这个问题。不同寻常的功能获得NOTCH1等位基因启动了强烈的下游信号，推动了异位T细胞的发展，并有效地诱导了白血病。相反，尽管仅启动微弱下游信号的功能获得等位基因也会诱导异位T细胞发育，但这些更常见的等位基因未能有效地启动白血病的发展。然而，弱功能获得的NOTCH1等位基因加速了由结构性激活的K-ras启动的白血病的发生，并导致了对Notch信号通路抑制敏感的肿瘤。这些数据表明，诱发白血病所需的Notch I剂量大于T细胞发育所需的剂量，而且在T-ALL细胞中发现的大多数NOTCH1突变不会产生足够强的信号来启动白血病的发展。此外，低水平、非白血病的Notch1可以补充其他白血病事件，如K-ras的激活。即使当Notch 1第二次参与时，所产生的肿瘤也显示出对Notch的“上瘾”，这为评估Notch信号通路抑制剂在白血病中的作用提供了进一步的理论基础。
Gain-of-function NOTCH1 mutations are found in 50%-70% of human T cell acute lymphoblastic leukemia/ lymphoma (T-ALL) cases. Gain-of-function NOTCH1 alleles that initiate strong downstream signals induce leukemia in mice, but it is unknown whether the gain-of-function NOTCH1 mutations most commonly found in individuals with T-ALL generate downstream signals of sufficient strength to induce leukemia. We addressed this question by expressing human gain-of-function NOTCH1 alleles of varying strength in mouse hematopoietic precursors. Uncommon gain-of-function NOTCH1 alleles that initiated strong downstream signals drove ectopic T cell development and induced leukemia efficiently. In contrast, although gain-of-function alleles that initiated only weak downstream signals also induced ectopic T cell development, these more common alleles failed to efficiently initiate leukemia development. However, weak gain-of-function NOTCH1 alleles accelerated the onset of leukemia initiated by constitutively active K-ras and gave rise to tumors that were sensitive to Notch signaling pathway inhibition. These data show that induction of leukemia requires doses of Notch I greater than those needed for T cell development and that most NOTCH1 mutations found in T-ALL cells do not generate signals of sufficient strength to initiate leukemia development. Furthermore, low, nonleukemogenic levels of Notch1 can complement other leukemogenic events, such as activation of K-ras. Even when Notch 1 participates secondarily, the resulting tumors show "addiction" to Notch, providing a further rationale for evaluating Notch signaling pathway inhibitors in leukemia.