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The novel lncRNA BlackMamba controls the neoplastic phenotype of ALK- anaplastic large cell lymphoma by regulating the DNA helicase HELLS.
Leukemia ( IF 12.8 ) Pub Date : 2020-03-02 , DOI: 10.1038/s41375-020-0754-8
Valentina Fragliasso 1 , Akanksha Verma 2, 3 , Gloria Manzotti 1 , Annalisa Tameni 1, 4 , Rohan Bareja 2 , Tayla B Heavican 5 , Javeed Iqbal 5 , Rui Wang 6 , Danilo Fiore 6 , Valentina Mularoni 1 , Wing C Chan 7 , Priscillia Lhoumaud 8 , Jane Skok 8 , Eleonora Zanetti 9 , Francesco Merli 10 , Alessia Ciarrocchi 1 , Oliver Elemento 2 , Giorgio Inghirami 6
Affiliation  

The molecular mechanisms leading to the transformation of anaplastic lymphoma kinase negative (ALK-) anaplastic large cell lymphoma (ALCL) have been only in part elucidated. To identify new culprits which promote and drive ALCL, we performed a total transcriptome sequencing and discovered 1208 previously unknown intergenic long noncoding RNAs (lncRNAs), including 18 lncRNAs preferentially expressed in ALCL. We selected an unknown lncRNA, BlackMamba, with an ALK- ALCL preferential expression, for molecular and functional studies. BlackMamba is a chromatin-associated lncRNA regulated by STAT3 via a canonical transcriptional signaling pathway. Knockdown experiments demonstrated that BlackMamba contributes to the pathogenesis of ALCL regulating cell growth and cell morphology. Mechanistically, BlackMamba interacts with the DNA helicase HELLS controlling its recruitment to the promoter regions of cell-architecture-related genes, fostering their expression. Collectively, these findings provide evidence of a previously unknown tumorigenic role of STAT3 via a lncRNA-DNA helicase axis and reveal an undiscovered role for lncRNA in the maintenance of the neoplastic phenotype of ALK-ALCL.

中文翻译:

新型 lncRNA BlackMamba 通过调节 DNA 解旋酶 HELLS 来控制 ALK 间变性大细胞淋巴瘤的肿瘤表型。

导致间变性淋巴瘤激酶阴性 (ALK-) 间变性大细胞淋巴瘤 (ALCL) 转化的分子机制仅部分阐明。为了确定促进和驱动 ALCL 的新罪魁祸首,我们进行了总转录组测序,发现了 1208 个以前未知的基因间长非编码 RNA (lncRNA),其中包括 18 个优先在 ALCL 中表达的 lncRNA。我们选择了一种未知的 lncRNA,BlackMamba,具有 ALK-ALCL 优先表达,用于分子和功能研究。BlackMamba 是一种染色质相关的 lncRNA,由 STAT3 通过典型的转录信号通路调节。击倒实验表明,BlackMamba 有助于 ALCL 的发病机制,调节细胞生长和细胞形态。机械地,BlackMamba 与 DNA 解旋酶 HELLS 相互作用,控制其募集到细胞结构相关基因的启动子区域,促进它们的表达。总的来说,这些发现提供了 STAT3 通过 lncRNA-DNA 解旋酶轴的先前未知的致瘤作用的证据,并揭示了 lncRNA 在维持 ALK-ALCL 肿瘤表型中未发现的作用。
更新日期:2020-03-02
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