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Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Item Type:Article
Title:Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms
Creators Name:Jayavelu, A.K. and Schnöder, T.M. and Perner, F. and Herzog, C. and Meiler, A. and Krishnamoorthy, G. and Huber, N. and Mohr, J. and Edelmann-Stephan, B. and Austin, R. and Brandt, S. and Palandri, F. and Schröder, N. and Isermann, B. and Edlich, F. and Sinha, A.U. and Ungelenk, M. and Hübner, C.A. and Zeiser, R. and Rahmig, S. and Waskow, C. and Coldham, I. and Ernst, T. and Hochhaus, A. and Jilg, S. and Jost, P.J. and Mullally, A. and Bullinger, L. and Mertens, P.R. and Lane, S.W. and Mann, M. and Heidel, F.H.
Abstract:Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system and in haematopoietic cancers. 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, 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.
Keywords:Apoptosis, Cell Line, Clone Cells, Cultured Cells, Heterografts, Intracellular Signaling Peptides and Proteins, Introns, Janus Kinase 2, MAP Kinase Signaling System, Mutation, Neoplasm Transplantation, Neoplasms, Phosphoproteins, Protein-Serine-Threonine Kinases, Proteome, Proteomics, RNA Splicing, Remission Induction, Y-Box-Binding Protein 1, Animals, Mice
Publisher:Nature Publishing Group
Page Range:157-163
Date:3 December 2020
Additional Information:Copyright © 2020 The Author(s).
Official Publication:https://doi.org/10.1038/s41586-020-2968-3
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