In T lymphocytes, the Wiskott-Aldrich Syndrome protein (WASP) and WASP-interacting-protein (WIP) regulate T cell antigen receptor (TCR) signaling, but their role in lymphoma is largely unknown. Here we show that the expression of WASP and WIP is frequently low or absent in anaplastic large cell lymphoma (ALCL) compared to other T cell lymphomas. In anaplastic lymphoma kinase-positive (ALK+) ALCL, WASP and WIP expression is regulated by ALK oncogenic activity via its downstream mediators STAT3 and C/EBP-β. ALK+ lymphomas were accelerated in WASP- and WIP-deficient mice. In the absence of WASP, active GTP-bound CDC42 was increased and the genetic deletion of one CDC42 allele was sufficient to impair lymphoma growth. WASP-deficient lymphoma showed increased mitogen-activated protein kinase (MAPK) pathway activation that could be exploited as a therapeutic vulnerability. Our findings demonstrate that WASP and WIP are tumor suppressors in T cell lymphoma and suggest that MAP-kinase kinase (MEK) inhibitors combined with ALK inhibitors could achieve a more potent therapeutic effect in ALK+ ALCL.

中文翻译：

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Wiskott-Aldrich 综合征蛋白 (WASP) 是 T 细胞淋巴瘤中的一种肿瘤抑制因子。

在 T 淋巴细胞中，Wiskott-Aldrich 综合征蛋白 (WASP) 和 WASP 相互作用蛋白 (WIP) 调节 T 细胞抗原受体 (TCR) 信号传导，但它们在淋巴瘤中的作用在很大程度上是未知的。在这里，我们显示与其他 T 细胞淋巴瘤相比，间变性大细胞淋巴瘤 (ALCL) 中 WASP 和 WIP 的表达通常较低或不存在。在间变性淋巴瘤激酶阳性 (ALK+) ALCL 中，WASP 和 WIP 表达受 ALK 致癌活性通过其下游介质 STAT3 和 C/EBP-β 调节。ALK+ 淋巴瘤在 WASP 和 WIP 缺陷小鼠中加速。在没有 WASP 的情况下，活性 GTP 结合的 CDC42 增加，一个 CDC42 等位基因的遗传缺失足以损害淋巴瘤的生长。WASP 缺陷型淋巴瘤表现出增加的丝裂原活化蛋白激酶 (MAPK) 通路激活，可用作治疗易损性。我们的研究结果表明 WASP 和 WIP 是 T 细胞淋巴瘤中的肿瘤抑制因子，并表明 MAP 激酶激酶 (MEK) 抑制剂与 ALK 抑制剂联合可以在 ALK+ ALCL 中获得更有效的治疗效果。