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Lymphoma

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

Leukemia volume 34, pages 2964–2980 (2020)Cite this article

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Abstract

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.

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Fig. 1: ALCL samples expressed a restricted set of aberrantly activated previously unknown lncRNAs.
Fig. 2: BlackMamba is a previously unknown long noncoding RNA in ALK− ALCL subset.
Fig. 3: STAT3 regulates BlackMamba expression.
Fig. 4: Loss of BlackMamba leads to impaired cell proliferation and clonogenicity of ALK− ALCL cells.
Fig. 5: BlackMamba regulates the lymphoid-specific helicase HELLS.
Fig. 6: BlackMamba controls the recruitment of HELLS on multiple target promoters.
Fig. 7: Silencing of HELLS mimics BlackMamba silencing phenotype.

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Data availability

BlackMamba sequence has been deposited in GenBank database with the accession number MN902222.

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Acknowledgements

We thank Dr Alan Epstein, who provided the TLBR-1 and 2 cells lines. We also thank Marina Grassi for technical help and Jacqueline Costa for English editing. This work was funded by the Italian Association for Cancer Research Special Program in Clinical Molecular Oncology, Milan (5 × 1000 No. 10007, GI), 7011-16 SCOR grant from the Leukemia & Lymphoma Society/SCOR grant (GI), by the Ministero della Salute (Ricerca Finalizzata No. GR-2016-02364298, VF), and R35GM122515 (JS). We thank the Epigenetic Core at Weill Cornell Medicine and the Genome Technology Center at New York University and GRADE Onlus Foundation.

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Authors and Affiliations

  1. Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy

    Valentina Fragliasso, Gloria Manzotti, Annalisa Tameni, Valentina Mularoni & Alessia Ciarrocchi

  2. Institute for Computational Biomedicine & Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA

    Akanksha Verma, Rohan Bareja & Oliver Elemento

  3. Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY, 10065, USA

    Akanksha Verma

  4. Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, 41125, Italy

    Annalisa Tameni

  5. Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68182, USA

    Tayla B. Heavican & Javeed Iqbal

  6. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA

    Rui Wang, Danilo Fiore & Giorgio Inghirami

  7. Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA

    Wing C. Chan

  8. Department of Pathology, New York University School of Medicine, Langone Medical Center, New York, NY, 10016, USA

    Priscillia Lhoumaud & Jane Skok

  9. Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy

    Eleonora Zanetti

  10. Hematology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy

    Francesco Merli

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  1. Valentina Fragliasso
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Contributions

All authors contributed as a team to the experimental design and the interpretation of data. VF, AT, GM, and VM performed experiments and data analysis. AV and RB performed bioinformatics analysis. OE supervised bioinformatics analysis. EZ performed FISH staining. GI, JI, TBH, FM, and VF diagnosed and stratified pathological samples. RW and DF performed the sequencing. VF and GI created the pathological and clinical database. PL, WC, and JK contributed to the data analyses. GI, VF, and AC wrote the manuscript.

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Correspondence to Alessia Ciarrocchi, Oliver Elemento or Giorgio Inghirami.

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Fragliasso, V., Verma, A., Manzotti, G. et al. The novel lncRNA BlackMamba controls the neoplastic phenotype of ALK− anaplastic large cell lymphoma by regulating the DNA helicase HELLS. Leukemia 34, 2964–2980 (2020). https://doi.org/10.1038/s41375-020-0754-8

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