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  Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Jayavelu, A. K., Schnöder, T., Perner, F., Herzog, C., Meiler, A., Krishnamoorthy, G., et al. (2020). Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms. Nature, 588, 157-163. doi:10.1038/s41586-020-2968-3.

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https://rdcu.be/ccxXF (Publisher version)
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Jayavelu, Ashok Kumar1, Author              
Schnöder, T.M.2, Author
Perner, F.2, Author
Herzog, C.2, Author
Meiler, Arno3, Author              
Krishnamoorthy, Gurumoorthy4, Author              
Huber, N.2, Author
Mohr, J.2, Author
Edelmann-Stephan, B.2, Author
Austin, R.2, Author
Brandt, S.2, Author
Palandri, F.2, Author
Schröder, N.2, Author
Isermann, B.2, Author
Edlich, F.2, Author
Sinha, A.U.2, Author
Ungelenk, M.2, Author
Hübner, C.A.2, Author
Zeiser, R.2, Author
Rahmig, S.2, Author
Waskow, C.2, AuthorColdham, I.2, AuthorErnst, T.2, AuthorHochhaus, A.2, AuthorJilg, S.2, AuthorJost, P.J.2, AuthorMullally, A.2, AuthorBullinger, L.2, AuthorMertens, P.R.2, AuthorLane, S.W.2, AuthorMann, Matthias1, Author              Heidel, F.H.2, Author more..
Affiliations:
1Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
2external, ou_persistent22              
3Pichlmair, Andreas / Innate Immunity, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565166              
4Krishnamoorthy, Gurumoorthy / Neuroinflammation and Mucosal Immunology, Max Planck Institute of Biochemistry, Max Planck Society, ou_2173635              

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Free keywords: Janus kinase 2, messenger RNA, mitogen activated protein kinase, Y box binding protein 1, apoptosis, cell component, experimental study, gene expression, inhibition, mutation, protein, RNA, rodent, adult, animal cell, animal experiment, apoptosis, Article, cohort analysis, controlled study, enzyme inactivation, enzyme inhibition, female, gene mutation, gene targeting, genetic transcription, human, human cell, human tissue, in vivo study, intron, JAK2 gene, major clinical study, male, MAPK signaling, mouse, myeloproliferative neoplasm, nonhuman, phosphoproteomics, priority journal, protein fingerprinting, protein phosphorylation, protein processing, RNA processing, RNA splicing
 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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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 Dates: 20182020-092020-112020
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Type: Peer
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 588 Sequence Number: - Start / End Page: 157 - 163 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238