Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:588 |
|---|---|
| Enthalten in: |
Nature - 588(2020), 7836 vom: 25. Dez., Seite 157-163 |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 05.02.2021 Date Revised 04.12.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41586-020-2968-3 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM318063700 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM318063700 | ||
| 003 | DE-627 | ||
| 005 | 20231225164556.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41586-020-2968-3 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1060.xml |
| 035 | |a (DE-627)NLM318063700 | ||
| 035 | |a (NLM)33239784 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Jayavelu, Ashok Kumar |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.02.2021 | ||
| 500 | |a Date Revised 04.12.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Phosphoproteins |2 NLM | |
| 650 | 7 | |a Proteome |2 NLM | |
| 650 | 7 | |a Y-Box-Binding Protein 1 |2 NLM | |
| 650 | 7 | |a YBX1 protein, human |2 NLM | |
| 650 | 7 | |a MKNK1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.1.- |2 NLM | |
| 650 | 7 | |a JAK2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Janus Kinase 2 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Protein Serine-Threonine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 700 | 1 | |a Schnöder, Tina M |e verfasserin |4 aut | |
| 700 | 1 | |a Perner, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a Herzog, Carolin |e verfasserin |4 aut | |
| 700 | 1 | |a Meiler, Arno |e verfasserin |4 aut | |
| 700 | 1 | |a Krishnamoorthy, Gurumoorthy |e verfasserin |4 aut | |
| 700 | 1 | |a Huber, Nicolas |e verfasserin |4 aut | |
| 700 | 1 | |a Mohr, Juliane |e verfasserin |4 aut | |
| 700 | 1 | |a Edelmann-Stephan, Bärbel |e verfasserin |4 aut | |
| 700 | 1 | |a Austin, Rebecca |e verfasserin |4 aut | |
| 700 | 1 | |a Brandt, Sabine |e verfasserin |4 aut | |
| 700 | 1 | |a Palandri, Francesca |e verfasserin |4 aut | |
| 700 | 1 | |a Schröder, Nicolas |e verfasserin |4 aut | |
| 700 | 1 | |a Isermann, Berend |e verfasserin |4 aut | |
| 700 | 1 | |a Edlich, Frank |e verfasserin |4 aut | |
| 700 | 1 | |a Sinha, Amit U |e verfasserin |4 aut | |
| 700 | 1 | |a Ungelenk, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Hübner, Christian A |e verfasserin |4 aut | |
| 700 | 1 | |a Zeiser, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Rahmig, Susann |e verfasserin |4 aut | |
| 700 | 1 | |a Waskow, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Coldham, Iain |e verfasserin |4 aut | |
| 700 | 1 | |a Ernst, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Hochhaus, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Jilg, Stefanie |e verfasserin |4 aut | |
| 700 | 1 | |a Jost, Philipp J |e verfasserin |4 aut | |
| 700 | 1 | |a Mullally, Ann |e verfasserin |4 aut | |
| 700 | 1 | |a Bullinger, Lars |e verfasserin |4 aut | |
| 700 | 1 | |a Mertens, Peter R |e verfasserin |4 aut | |
| 700 | 1 | |a Lane, Steven W |e verfasserin |4 aut | |
| 700 | 1 | |a Mann, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Heidel, Florian H |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature |d 1945 |g 588(2020), 7836 vom: 25. Dez., Seite 157-163 |w (DE-627)NLM000008257 |x 1476-4687 |7 nnns |
| 773 | 1 | 8 | |g volume:588 |g year:2020 |g number:7836 |g day:25 |g month:12 |g pages:157-163 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41586-020-2968-3 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 588 |j 2020 |e 7836 |b 25 |c 12 |h 157-163 | ||