Epitranscriptomic modifications in acute myeloid leukemia: m6A and 2′-O-methylation as targets for novel therapeutic strategies

Cornelius Pauli; Michael Kienhöfer; Stefanie Göllner; Carsten Müller-Tidow

doi:10.1515/hsz-2021-0286

Article

Epitranscriptomic modifications in acute myeloid leukemia: m⁶A and 2′-O-methylation as targets for novel therapeutic strategies

Cornelius Pauli

Cornelius Pauli finished his medical studies at the University of Halle (Saale) in 2019. During his studies he joined the group of Carsten Müller-Tidow to work on the functional role of snoRNAs in Acute Myeloid Leukemia. At the moment he is working as a physician scientist in the group of Michaela Frye at the DKFZ Heidelberg and in the group of Carsten Müller-Tidow at the University Hospital Heidelberg. His current research interest is focused on RNA modifications in AML.
, Michael Kienhöfer

Michael Kienhöfer is a 4th year medical student at the Ruprecht-Karls-University of Heidelberg. Recently, he joined the group of Carsten Müller-Tidow to work on his medical doctorate. In collaboration with Cornelius Pauli, he aims to gain insight in RNA modifying enzymes utilizing them as new therapeutic targets in AML.
, Stefanie Göllner

Stefanie Göllner is a senior scientist in the workgroup “Epigenomics, Epitranscriptomics and Novel Therapy Approaches in AML” at the University Hospital Heidelberg. She studied Biology and graduated at the Friedrich-Schiller-University in Jena. She worked as a Postdoc at the University Hospitals Münster and Halle (Saale) in the group of Carsten Müller-Tidow. Her current work focuses on the impact of epigenetic mechanisms on pathogenesis and therapy resistance in AML. Besides her interest in exploring mechanisms that drive leukemia, she is also enthusiastic about research management and scientific writing.
and Carsten Müller-Tidow

Carsten Müller-Tidow is currently Director of the Department of Hematology, Oncology and Rheumatology at the University Hospital in Heidelberg and a member of the Molecular Medicine Partnership of UKHD-EMBL. He did his Residency and Fellowship at the University Hospital in Münster where he became Professor in 2009. Carsten Müller-Tidow was a member of the IZKF Münster and his projects were supported by the IZKF for more than 10 years. In 2014, he became Director of the Department of Hematology and Oncology at the University Hospital Halle (Saale). In 2017 he moved to Heidelberg. His scientific interests focus on translation of basic research findings into clinical trials especially in hematological malignancies.

Published/Copyright: October 11, 2021

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From the journal Biological Chemistry Volume 402 Issue 12

Abstract

Modifications of RNA commonly occur in all species. Multiple enzymes are involved as writers, erasers and readers of these modifications. Many RNA modifications or the respective enzymes are associated with human disease and especially cancer. Currently, the mechanisms how RNA modifications impact on a large number of intracellular processes are emerging and knowledge about the pathogenetic role of RNA modifications increases. In Acute Myeloid Leukemia (AML), the N ⁶-methyladenosine (m⁶A) modification has emerged as an important modulator of leukemogenesis. The writer proteins METTL3 and METTL14 are both involved in AML pathogenesis and might be suitable therapeutic targets. Recently, close links between 2′-O-methylation (2′-O-me) of ribosomal RNA and leukemogenesis were discovered. The AML1-ETO oncofusion protein which specifically occurs in a subset of AML was found to depend on induction of snoRNAs and 2′-O-me for leukemogenesis. Also, NPM1, an important tumor suppressor in AML, was associated with altered snoRNAs and 2′-O-me. These findings point toward novel pathogenetic mechanisms and potential therapeutic interventions. The current knowledge and the implications are the topic of this review.

Keywords: 2′-O-methylation; acute myeloid leukemia; epitranscriptome; m6A; RNA modifications; snoRNAs

Corresponding author: Carsten Müller-Tidow, Department of Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; and Molecular Medicine Partnership Unit, European Molecular Biology Laboratory (EMBL)–Heidelberg University Hospital, 69117 Heidelberg, Germany; and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany, E-mail: Carsten.Mueller-tidow@med.uni-heidelberg.de

Cornelius Pauli and Michael Kienhöfer have contributed equally to this work. This article is a contribution to the issue highlighting the 25th Anniversary of the Interdisciplinary Centre for Clinical Research (IZKF) Münster.

Funding source: Dieter Morszeck Foundation

Award Identifier / Grant number: DKFZ Clinician Scientist Program

About the authors

Cornelius Pauli

Cornelius Pauli finished his medical studies at the University of Halle (Saale) in 2019. During his studies he joined the group of Carsten Müller-Tidow to work on the functional role of snoRNAs in Acute Myeloid Leukemia. At the moment he is working as a physician scientist in the group of Michaela Frye at the DKFZ Heidelberg and in the group of Carsten Müller-Tidow at the University Hospital Heidelberg. His current research interest is focused on RNA modifications in AML.

Michael Kienhöfer

Michael Kienhöfer is a 4th year medical student at the Ruprecht-Karls-University of Heidelberg. Recently, he joined the group of Carsten Müller-Tidow to work on his medical doctorate. In collaboration with Cornelius Pauli, he aims to gain insight in RNA modifying enzymes utilizing them as new therapeutic targets in AML.

Stefanie Göllner

Stefanie Göllner is a senior scientist in the workgroup “Epigenomics, Epitranscriptomics and Novel Therapy Approaches in AML” at the University Hospital Heidelberg. She studied Biology and graduated at the Friedrich-Schiller-University in Jena. She worked as a Postdoc at the University Hospitals Münster and Halle (Saale) in the group of Carsten Müller-Tidow. Her current work focuses on the impact of epigenetic mechanisms on pathogenesis and therapy resistance in AML. Besides her interest in exploring mechanisms that drive leukemia, she is also enthusiastic about research management and scientific writing.

Carsten Müller-Tidow

Carsten Müller-Tidow is currently Director of the Department of Hematology, Oncology and Rheumatology at the University Hospital in Heidelberg and a member of the Molecular Medicine Partnership of UKHD-EMBL. He did his Residency and Fellowship at the University Hospital in Münster where he became Professor in 2009. Carsten Müller-Tidow was a member of the IZKF Münster and his projects were supported by the IZKF for more than 10 years. In 2014, he became Director of the Department of Hematology and Oncology at the University Hospital Halle (Saale). In 2017 he moved to Heidelberg. His scientific interests focus on translation of basic research findings into clinical trials especially in hematological malignancies.

Acknowledgments

Michael Kienhöfer is promoted by a doctoral scholarship of the German Society for Hematology and Oncology (DGHO) in cooperation with the German José Carreras Foundation. The authors thank Daniel Heid for careful reading of the manuscript. The Figures were created with Biorender.com.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: Cornelius Pauli has been funded by a fellowship of the DKFZ Clinician Scientist Program, supported by the Dieter Morszeck Foundation.
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

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Received: 2021-06-08

Accepted: 2021-09-24

Published Online: 2021-10-11

Published in Print: 2021-11-25

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Articles in the same Issue

https://doi.org/10.1515/hsz-2021-0286

Keywords for this article

2′-O-methylation; acute myeloid leukemia; epitranscriptome; m6A; RNA modifications; snoRNAs