Bandini Cecilia, Pupuleku Aldi, Spaccarotella Elisa, Pellegrino Elisa, Wang Rui, Vitale Nicoletta, Duval Carlotta, Cantarella Daniela, Rinaldi Andrea, Provero Paolo, Di Cunto Ferdinando, Medico Enzo, Bertoni Francesco, Inghirami Giorgio, Piva Roberto
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino 10126, Italy.
Cancers (Basel). 2018 Jan 18;10(1):21. doi: 10.3390/cancers10010021.
Systemic anaplastic large cell lymphomas (ALCL) are a category of T-cell non-Hodgkin's lymphomas which can be divided into anaplastic lymphoma kinase (ALK) positive and ALK negative subgroups, based on ALK gene rearrangements. Among several pathways aberrantly activated in ALCL, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) is shared by all ALK positive ALCL and has been detected in a subgroup of ALK negative ALCL. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we combined gene expression profiling analysis and RNA interference functional approaches. A shRNA screening of STAT3-modulated genes identified interferon regulatory factor 4 (IRF4) as a key driver of ALCL cell survival. Accordingly, ectopic IRF4 expression partially rescued STAT3 knock-down effects. Treatment with immunomodulatory drugs (IMiDs) induced IRF4 down regulation and resulted in cell death, a phenotype rescued by IRF4 overexpression. However, the majority of ALCL cell lines were poorly responsive to IMiDs treatment. Combination with JQ1, a bromodomain and extra-terminal (BET) family antagonist known to inhibit MYC and IRF4, increased sensitivity to IMiDs. Overall, these results show that IRF4 is involved in STAT3-oncogenic signaling and its inhibition provides alternative avenues for the design of novel/combination therapies of ALCL.
系统性间变性大细胞淋巴瘤（ALCL）是一类T细胞非霍奇金淋巴瘤，根据间变性淋巴瘤激酶（ALK）基因重排可分为ALK阳性和ALK阴性亚组。在ALCL中异常激活的几种信号通路中，信号转导和转录激活因子3（STAT3）的组成性激活在所有ALK阳性ALCL中均有体现，并且在一部分ALK阴性ALCL中也被检测到。为了发现可能代表ALCL治疗可行靶点的STAT3致癌活性的关键介质，我们结合了基因表达谱分析和RNA干扰功能方法。对STAT3调控基因的shRNA筛选确定干扰素调节因子4（IRF4）是ALCL细胞存活的关键驱动因素。因此，异位IRF4表达部分挽救了STAT3敲低的效应。用免疫调节药物（IMiDs）治疗可诱导IRF4下调并导致细胞死亡，这种表型可通过IRF4过表达来挽救。然而，大多数ALCL细胞系对IMiDs治疗反应不佳。与已知可抑制MYC和IRF4的溴结构域和额外末端（BET）家族拮抗剂JQ1联合使用，可增加对IMiDs的敏感性。总体而言，这些结果表明IRF4参与STAT3致癌信号传导，其抑制为ALCL新型/联合疗法的设计提供了替代途径。
