Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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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
Web of Science PubMed FullText FullText_MUG

Co-Autor*innen der Med Uni Graz: Jost Philipp
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Abstract:: Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells^1,2. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system^3,4 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 clones^6,7, 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 JAK2^V617F 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