Bellavia Diana, Campese Antonio F, Checquolo Saula, Balestri Anna, Biondi Andrea, Cazzaniga Giovanni, Lendahl Urban, Fehling Hans J, Hayday Adrian C, Frati Luigi, von Boehmer Harald, Gulino Alberto, Screpanti Isabella
Department of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 324, 00161 Roma, Italy.
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3788-93. doi: 10.1073/pnas.062050599. Epub 2002 Mar 12.
Notch receptors are conserved regulators of cell fate and have been implicated in the regulation of T cell differentiation and lymphomagenesis. However, neither the generality of Notch involvement in leukemia, nor the molecules with which Notch may interact have been clarified. Recently, we showed that transgenic mice expressing the constitutively active intracellular domain of Notch3 in thymocytes and T cells developed early and aggressive T cell neoplasias. Although primarily splenic, the tumors sustained features of immature thymocytes, including expression of pTalpha, a defining component of the pre T cell receptor, known to be a potent signaling complex provoking thymocyte survival, proliferation, and activation. Thus, enforced expression of Notch3, which is ordinarily down-regulated as thymocytes mature, may sustain pre T cell receptor expression, causing dysregulated hyperplasia. This hypothesis has been successfully tested in this article by the observation that deletion of pTalpha in Notch3 transgenic mice abrogates tumor development, indicating a crucial role for pTalpha in T cell leukemogenesis. Parallel observations were made in humans, in that all T cell acute lymphoblastic leukemias examined showed expression of Notch3 and of the Notch target gene HES-1, as well as of pTalpha a and b transcripts, whereas the expression of all these genes was dramatically reduced or absent in remission. Together, these results suggest that the combined expression of Notch3 and pTalpha sustains T cell leukemogenesis and may represent pathognomonic molecular features of human T-ALL.
Notch受体是细胞命运的保守调节因子，参与T细胞分化和淋巴瘤发生的调控。然而，Notch在白血病中的普遍作用以及Notch可能相互作用的分子尚未明确。最近，我们发现，在胸腺细胞和T细胞中表达组成性激活的Notch3细胞内结构域的转基因小鼠发生了早期侵袭性T细胞肿瘤。尽管肿瘤主要发生在脾脏，但具有未成熟胸腺细胞的特征，包括前T细胞受体的决定性成分pTα的表达，已知pTα是一种有效的信号复合物，可促进胸腺细胞存活、增殖和激活。因此，通常在胸腺细胞成熟时被下调的Notch3的强制表达可能维持前T细胞受体的表达，导致增生失调。本文通过观察Notch3转基因小鼠中pTα的缺失消除肿瘤发展，成功验证了这一假设，表明pTα在T细胞白血病发生中起关键作用。在人类中也有类似观察结果，即所有检测的T细胞急性淋巴细胞白血病均显示Notch3、Notch靶基因HES-1以及pTα a和b转录本的表达，而在缓解期所有这些基因的表达显著降低或缺失。这些结果共同表明，Notch3和pTα的联合表达维持T细胞白血病发生，可能代表人类T-ALL的特征性分子特征。
