Page 26 - Haematologica May 2022

Acute Myeloid Leukemia
Ferrata Storti Foundation
Haematologica 2022 Volume 107(5):1034-1044
Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia
Dimitrios Papaioannou,1,2* Hatice G. Ozer,3* Deedra Nicolet,1,4,5 Amog P. Urs,1 Tobias Herold,6-9 Krzysztof Mrózek,1,4 Aarif M.N. Batcha,10,11 Klaus H. Metzeler,12 Ayse S. Yilmaz,3 Stefano Volinia,13 Marius Bill,1 Jessica Kohlschmidt,1,4,5 Maciej Pietrzak,3 Christopher J. Walker,1,4 Andrew J. Carroll,14 Jan Braess,15 Bayard L. Powell,16 Ann-Kathrin Eisfeld,1,4 Geoffrey L. Uy,17 Eunice S. Wang,18 Jonathan E. Kolitz,19 Richard M. Stone,20 Wolfgang Hiddemann,6-8 John C. Byrd,1,4 Clara D. Bloomfield1# and Ramiro Garzon1#
1The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA; 2Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY, USA; 3The Ohio State University, Department of Biomedical Informatics, Columbus, OH, USA; 4The Ohio State University Comprehensive Cancer Center, Clara D. Bloomfield Center for Leukemia Outcomes Research, Columbus, OH, USA; 5Alliance Statistics and Data Center, The Ohio State University, Comprehensive Cancer Center, Columbus, OH, USA; 6Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany; 7German Cancer Consortium (DKTK), Heidelberg, Germany; 8German Cancer Research Center (DKFZ), Heidelberg, Germany; 9Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), Munich, Germany; 10Institute for Medical Information Processing, Biometry and Epidemiology, LMU Munich, Munich, Germany; 11Medical Data Integration Center (MeDIC), University Hospital, LMU Munich, Germany; 12Department of Hematology, Cell Therapy & Hemostaseology, University Hospital Leipzig, Leipzig, Germany; 13Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy; 14Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA; 15Department of Oncology and Hematology, Hospital Barmherzige Brüder, Regensburg, Germany; 16The Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA; 17Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA; 18Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; 19Monter Cancer Center, Hofstra Northwell School of Medicine, Lake Success, NY, USA and 20Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA
*DP and HGO contributed equally as co-first authors. #CDB and RG contributed equally as co-senior authors.
ABSTRACT
Expression levels of long non-coding RNA (lncRNA) have been shown to associate with clinical outcome of patients with cytoge- netically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNA in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged <60 years) with CN-AML, who were comprehensively characterized with regard to clin- ical outcome. We used available genomic databases and stringent filters to annotate genetic variants unequivocally located in the non-coding transcriptome of AML patients. We detected 981 variants, which are recurrently present in lncRNA that are expressed in leukemic blasts. Among these variants, we identified a cytosine-to-thymidine variant in the lncRNA RP5-1074L1.4 and a cytosine-to-thymidine variant in the lncRNA SNHG15, which independently associated with longer survival of CN-AML patients. The presence of the SNHG15 cytosine-to-thymi- dine variant was also found to associate with better outcome in an inde- pendent dataset of CN-AML patients, despite differences in treatment protocols and RNA sequencing techniques. In order to gain biological insights, we cloned and overexpressed both wild-type and variant ver-
Correspondence:
RAMIRO GARZON
ramiro.garzon@osumc.edu
Received: July 21, 2020. Accepted: July 2, 2021. Pre-published: July 15, 2021.
https://doi.org/10.3324/haematol.2020.266643 ©2022 Ferrata Storti Foundation
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