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

Authors
  • Fragliasso, Valentina1
  • Verma, Akanksha2, 3
  • Manzotti, Gloria1
  • Tameni, Annalisa1, 4
  • Bareja, Rohan2
  • Heavican, Tayla B5
  • Iqbal, Javeed5
  • Wang, Rui6
  • Fiore, Danilo6
  • Mularoni, Valentina1
  • Chan, Wing C7
  • Lhoumaud, Priscillia8
  • Skok, Jane8
  • Zanetti, Eleonora9
  • Merli, Francesco10
  • Ciarrocchi, Alessia11
  • Elemento, Oliver12
  • Inghirami, Giorgio13
  • 1 Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy. , (Italy)
  • 2 Institute for Computational Biomedicine & Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA. , (Israel)
  • 3 Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY, 10065, USA.
  • 4 Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, 41125, Italy. , (Italy)
  • 5 Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68182, USA.
  • 6 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 7 Department of Pathology, City of Hope National Medical Center, Duarte, CA, 91010, USA.
  • 8 Department of Pathology, New York University School of Medicine, Langone Medical Center, New York, NY, 10016, USA.
  • 9 Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy. , (Italy)
  • 10 Hematology Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy. , (Italy)
  • 11 Laboratory of Translational Research, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42123, Italy. [email protected] , (Italy)
  • 12 Institute for Computational Biomedicine & Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA. [email protected] , (Israel)
  • 13 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, 10065, USA. [email protected]
Type
Published Article
Journal
Leukemia
Publisher
Springer Nature
Publication Date
Nov 01, 2020
Volume
34
Issue
11
Pages
2964–2980
Identifiers
DOI: 10.1038/s41375-020-0754-8
PMID: 32123306
Source
Medline
Language
English
License
Unknown

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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