Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Ashok Kumar Jayavelu, Tina M. Schnöder, Florian Perner, Carolin Herzog, Arno Meiler, Gurumoorthy Krishnamoorthy, Nicolas Huber, Juliane Mohr, Bärbel Edelmann-Stephan, Rebecca Austin, Sabine Brandt, Francesca Palandri, Nicolas Schröder, Berend Isermann, Frank Edlich, Amit U. Sinha, Martin Ungelenk, Christian A. Hübner, Robert Zeiser, Susann Rahmig, Claudia Waskow, Iain Coldham, Thomas Ernst, Andreas Hochhaus, Stefanie Jilg, Philipp J. Jost, Ann Mullally, Lars Bullinger, Peter R. Mertens, Steven W. Lane, Matthias Mann () and Florian H. Heidel ()
Additional contact information
Ashok Kumar Jayavelu: Max Planck Institute of Biochemistry
Tina M. Schnöder: Universitätsklinikum Jena
Florian Perner: Universitätsklinikum Jena
Carolin Herzog: Otto von Guericke University Medical Center
Arno Meiler: Max Planck Institute of Biochemistry
Gurumoorthy Krishnamoorthy: Max Planck Institute of Biochemistry
Nicolas Huber: Universitätsklinikum Jena
Juliane Mohr: Universitätsklinikum Jena
Bärbel Edelmann-Stephan: Otto von Guericke University Medical Center
Rebecca Austin: QIMR Berghofer Medical Research Institute
Sabine Brandt: Otto von Guericke University Medical Center
Francesca Palandri: Azienda Ospedaliero–Universitaria di Bologna
Nicolas Schröder: Pathology, Klinikum Ernst-von-Bergmann
Berend Isermann: Otto von Guericke University Medical Center
Frank Edlich: University of Freiburg
Amit U. Sinha: Basepair Technology Inc
Martin Ungelenk: Universitätsklinikum Jena
Christian A. Hübner: Universitätsklinikum Jena
Robert Zeiser: University of Freiburg
Susann Rahmig: Leibniz Institute on Aging, Fritz Lipmann Institute
Claudia Waskow: Leibniz Institute on Aging, Fritz Lipmann Institute
Iain Coldham: University of Sheffield
Thomas Ernst: Universitätsklinikum Jena
Andreas Hochhaus: Universitätsklinikum Jena
Stefanie Jilg: Technische Universität München
Philipp J. Jost: Technische Universität München
Ann Mullally: Brigham and Women’s Hospital and Harvard Medical School
Lars Bullinger: Charite University
Peter R. Mertens: Otto von Guericke University Medical Center
Steven W. Lane: QIMR Berghofer Medical Research Institute
Matthias Mann: Max Planck Institute of Biochemistry
Florian H. Heidel: Universitätsklinikum Jena

Nature, 2020, vol. 588, issue 7836, 157-163

Abstract: Abstract Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells1,2. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system3,4 and in haematopoietic cancers5. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones6,7, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2–ERK signalling and the maintenance of JAK2V617F malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (3)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2968-3 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:588:y:2020:i:7836:d:10.1038_s41586-020-2968-3

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2968-3

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().