ALK–transformed mature T lymphocytes restores early thymus progenitor features

Anaplastic large cell lymphoma (ALCL) is a mature T cell neoplasm that often expresses the CD4+ T cell surface marker. (It usually harbors the t(2;5) (p23;q35) translocation, leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. We demonstrated that in vitro transduction of normal human CD4+ T lymphocytes with NPM-ALK results in their immortalization and malignant transformation. The tumor cells displayed morphological and immunophenotypical characteristics of primary patient–derived anaplastic large cell lymphomas. Cell growth, proliferation, and survival were strictly dependent on NPM-ALK activity and include activation of the key factors STAT3 and DNMT1 and expression of CD30 (the hallmark of anaplastic large-cell lymphoma). Implantation of NPM-ALK–transformed CD4+ T lymphocytes into immunodeficient mice resulted in the formation of tumors indistinguishable from patients' anaplastic large cell lymphomas. Integration of “Omic” data revealed that NPM-ALK–transformed CD4+ T lymphocytes and primary NPM-ALK+ ALCL biopsies share similarities with early T cell precursors. Of note, these NPM-ALK+ lymphoma cells overexpress stem cell regulators (OCT4, SOX2, and NANOG) and HIF2A, which is known to affect hematopoietic precursor differentiation and NPM-ALK+ cell growth. Altogether, for the first time our findings suggest that NPM-ALK could restore progenitor-like features in mature CD30+ peripheral CD4+ T cells, in keeping with a thymic progenitor-like pattern. Overall design: examination of origin of ALCL

间变性大细胞淋巴瘤（Anaplastic large cell lymphoma, ALCL）是一类常表达CD4+ T细胞表面标志物的成熟T细胞肿瘤。该肿瘤通常携带有t(2;5)(p23;q35)易位，可导致嵌合酪氨酸激酶NPM-ALK的异位表达。本研究证实，利用NPM-ALK对正常人CD4+ T淋巴细胞进行体外转导，可使其发生永生化与恶性转化。所得肿瘤细胞具备患者源性间变性大细胞淋巴瘤的形态学与免疫表型特征。细胞的生长、增殖与存活严格依赖NPM-ALK的活性，其机制涉及关键因子信号转导与转录激活因子3（STAT3）、DNA甲基转移酶1（DNMT1）的激活，以及间变性大细胞淋巴瘤的标志性分子CD30的表达。将经NPM-ALK转化的CD4+ T淋巴细胞移植至免疫缺陷小鼠体内，可形成与患者源性间变性大细胞淋巴瘤难以区分的肿瘤。整合组学（Omic）数据后发现，经NPM-ALK转化的CD4+ T淋巴细胞与原代NPM-ALK阳性ALCL活检组织，均与早期T细胞前体具有相似性。值得注意的是，此类NPM-ALK阳性淋巴瘤细胞高表达干细胞调控因子OCT4、SOX2、NANOG，以及已知可影响造血前体细胞分化与NPM-ALK阳性细胞生长的缺氧诱导因子2α（HIF2A）。综上，本研究首次表明，NPM-ALK可在成熟CD30+外周CD4+ T细胞中恢复祖细胞样特征，这与胸腺祖细胞样表型相符。整体实验设计：间变性大细胞淋巴瘤的起源分析。