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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Jayavelu, AK; Schnöder, TM; Perner, F; Herzog, C; Meiler, A; Krishnamoorthy, G; Huber, N; Mohr, J; Edelmann-Stephan, B; Austin, R; Brandt, S; Palandri, F; Schröder, N; Isermann, B; Edlich, F; Sinha, AU; Ungelenk, M; Hübner, CA; Zeiser, R; Rahmig, S; Waskow, C; Coldham, I; Ernst, T; Hochhaus, A; Jilg, S; Jost, PJ; Mullally, A; Bullinger, L; Mertens, PR; Lane, SW; Mann, M; Heidel, FH.
Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms.
Nature. 2020; 588(7836):157-163 Doi: 10.1038/s41586-020-2968-3
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Co-Autor*innen der Med Uni Graz
Jost Philipp

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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.
Find related publications in this database (using NLM MeSH Indexing)
Animals - administration & dosage
Apoptosis - drug effects
Cell Line - administration & dosage
Cells, Cultured - administration & dosage
Clone Cells - metabolism, pathology
Female - administration & dosage
Heterografts - administration & dosage
Humans - administration & dosage
Intracellular Signaling Peptides and Proteins - genetics, metabolism
Introns - genetics
Janus Kinase 2 - antagonists & inhibitors, genetics, metabolism
MAP Kinase Signaling System - drug effects
Male - administration & dosage
Mice - administration & dosage
Mutation - administration & dosage
Neoplasm Transplantation - administration & dosage
Neoplasms - drug therapy, genetics, pathology
Phosphoproteins - analysis
Phosphorylation - administration & dosage
Protein-Serine-Threonine Kinases - genetics, metabolism
Proteome - analysis
Proteomics - administration & dosage
RNA Splicing - genetics
Remission Induction - administration & dosage
Y-Box-Binding Protein 1 - antagonists & inhibitors, chemistry, metabolism

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