Chiang Mark Y, Xu Lanwei, Shestova Olga, Histen Gavin, L'heureux Sarah, Romany Candice, Childs M Eden, Gimotty Phyllis A, Aster Jon C, Pear Warren S
Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 2008 Sep;118(9):3181-94. doi: 10.1172/JCI35090.
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 Notch1 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 Notch1 participates secondarily, the resulting tumors show "addiction" to Notch, providing a further rationale for evaluating Notch signaling pathway inhibitors in leukemia.
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性NOTCH1突变。启动强烈下游信号的功能获得性NOTCH1等位基因可在小鼠中诱发白血病,但尚不清楚在T-ALL患者中最常见的功能获得性NOTCH1突变是否能产生足够强度的下游信号来诱发白血病。我们通过在小鼠造血前体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。启动强烈下游信号的罕见功能获得性NOTCH1等位基因驱动异位T细胞发育并有效诱发白血病。相比之下,虽然启动较弱下游信号的功能获得性等位基因也能诱导异位T细胞发育,但这些更常见的等位基因未能有效启动白血病发展。然而,弱功能获得性NOTCH1等位基因加速了由组成型活性K-ras引发的白血病的发病,并产生了对Notch信号通路抑制敏感的肿瘤。这些数据表明,白血病的诱发需要比T细胞发育所需剂量更高的Notch1,并且在T-ALL细胞中发现的大多数NOTCH1突变不会产生足够强度的信号来启动白血病发展。此外,低水平、非致白血病的Notch1可以补充其他致白血病事件,如K-ras的激活。即使Notch1是继发参与,所产生的肿瘤也表现出对Notch的“依赖性”,这为评估白血病中Notch信号通路抑制剂提供了进一步的理论依据。