Abstract

Long non-coding RNAs (lncRNAs) are important regulatory molecules that are implicated in cellular physiology and pathology. In this work, we dissect the functional role of the HOXB-AS3 lncRNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 is shown to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism, HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.

LncRNAs at the HOX gene locus are increased in expression in NPM1 mutant acute myeloid leukemia. In this study, the authors show that one such lncRNA, HOX3B-AS3, has a role in regulating gene transcription and protein synthesis in leukemia cells.

Details

Title
The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia
Author
Papaioannou Dimitrios 1 ; Petri, Andreas 2   VIAFID ORCID Logo  ; Dovey, Oliver M 3 ; Terreri Sara 4 ; Wang, Eric 5 ; Collins, Frances A 1 ; Woodward, Lauren A 6 ; Walker, Allison E 1 ; Nicolet Deedra 7 ; Pepe Felice 1   VIAFID ORCID Logo  ; Prasanthi, Kumchala 1 ; Bill, Marius 1 ; Walker, Christopher J 1 ; Karunasiri Malith 1 ; Mrózek Krzysztof 1 ; Gardner, Miranda L 8 ; Camilotto Virginia 9 ; Zitzer Nina 1 ; Cooper, Jonathan L 3 ; Cai Xiongwei 10 ; Rong-Mullins Xiaoqing 11   VIAFID ORCID Logo  ; Kohlschmidt Jessica 7 ; Archer, Kellie J 11   VIAFID ORCID Logo  ; Freitas, Michael A 8 ; Zheng, Yi 12 ; Lee, Robert J 13 ; Aifantis Iannis 5 ; Vassiliou, George 14   VIAFID ORCID Logo  ; Singh Guramrit 6   VIAFID ORCID Logo  ; Kauppinen Sakari 2 ; Bloomfield, Clara D 1   VIAFID ORCID Logo  ; Dorrance, Adrienne M 1 ; Garzon Ramiro 1 

1  The Ohio State University, Comprehensive Cancer Center, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
2  Aalborg University, Center for RNA Medicine, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5117.2) (ISNI:0000 0001 0742 471X) 
3  Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
4  Institute of Genetics and Biophysics (IGB-ABT), National Council of Research (CNR), Naples, Italy (GRID:grid.419869.b) (ISNI:0000 0004 1758 2860) 
5  New York University School of Medicine, Department of Pathology, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
6  The Ohio State University, Department of Molecular Genetics, Center for RNA Biology, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
7  The Ohio State University, Comprehensive Cancer Center, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943); The Ohio State University, Alliance for Clinical Trials in Oncology Statistics and Data Center, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
8  The Ohio State University, Comprehensive Cancer Center, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943); The Ohio State University, Department of Cancer Biology and Genetics, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
9  Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); University of Pavia, Department of Molecular Medicine, Pavia, Italy (GRID:grid.8982.b) (ISNI:0000 0004 1762 5736) 
10  Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cancer and Blood Diseases Institute, Cincinnati, USA (GRID:grid.10306.34) 
11  The Ohio State University, Comprehensive Cancer Center, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943); The Ohio State University, Division of Biostatistics, College of Public Health, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
12  Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cancer and Blood Diseases Institute, Cincinnati, USA (GRID:grid.261331.4) 
13  The Ohio State University, Division of Pharmaceutics, College of Pharmacy, Columbus, USA (GRID:grid.261331.4) (ISNI:0000 0001 2285 7943) 
14  Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382); Cambridge University Hospitals NHS Trust, Department of Haematology, Cambridge, UK (GRID:grid.24029.3d) (ISNI:0000 0004 0383 8386) 
Publication year
2019
Publication date
2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-019-13259-2
ProQuest document ID
2317925363
Copyright
© The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.