The novel lncRNA BlackMamba controls the neoplastic phenotype of ALK− anaplastic large cell lymphoma by regulating the DNA helicase HELLS

• Published in: Leukemia 2020-11, Vol.34 (11), p.2964-2980
• Main Authors: Fragliasso, Valentina, Verma, Akanksha, Manzotti, Gloria, Tameni, Annalisa, Bareja, Rohan, Heavican, Tayla B., Iqbal, Javeed, Wang, Rui, Fiore, Danilo, Mularoni, Valentina, Chan, Wing C., Lhoumaud, Priscillia, Skok, Jane, Zanetti, Eleonora, Merli, Francesco, Ciarrocchi, Alessia, Elemento, Oliver, Inghirami, Giorgio
• Format: Article
• Language: English
• Subjects: 38/89; 38/91; 631/67/69; 692/420; 96/1; Anaplastic large-cell lymphoma; Anaplastic Lymphoma Kinase - deficiency; Biopsy; Cancer Research; Cell Line, Tumor; Cell morphology; Cell Proliferation; Chromatin; Clonal Evolution; Critical Care Medicine; Cytology; Deoxyribonucleic acid; DNA; DNA helicase; DNA Helicases - genetics; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Hematology; Humans; Intensive; Internal Medicine; Kinases; Lymphoma; Lymphoma, Large-Cell, Anaplastic - genetics; Lymphoma, Large-Cell, Anaplastic - pathology; Medicine; Medicine & Public Health; MicroRNAs - genetics; Models, Biological; Molecular modelling; Morphology; Oncology; Pathogenesis; Phenotype; Phenotypes; Promoter Regions, Genetic; Protein-tyrosine kinase; RNA Interference; RNA, Long Noncoding; Signal transduction; Stat3 protein; Transcription
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-020-0754-8

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.