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Oroshi"],"technology_type":["Affinity purification coupled with mass spectrometry proteomics","Mass Spectrometry","Shotgun proteomics"],"disease":["Myeloproliferative Neoplasm"],"software":["Not available"],"submitter_keywords":["Erksignaling","Mpn","Phosphoproteome","Ybx1","Jak2","Splicing factor","Hematological malignancy"],"full_dataset_link":["http://www.ebi.ac.uk/pride/archive/projects/PXD006921"],"tissue":["Multipotent Stem Cell","Primary Cell","Blood Cell","Monocyte","Leukocyte","Stem Cell","Cell Culture","Neutrophil","Bone Marrow","Blood"],"sample_protocol":["Samples were processed according to the protocol previously described. Briefly, samples were collected as quadruplicate biological replicates for each condition, lysed in Gmdcl buffer (6M Gdmcl, 100mM Tris pH8.5, 10mM TCEP and 40mM CAA), heated for 5 mins at 95°C and cooled on ice for 15min. Lysed samples were then sonicated (Branson probe sonifier output 3-4, 50% duty cycle, 10x 30 sec) and heated again. Proteins were precipitated with acetone, BCA quantified. 2mg were digested with LysC and Trypsin overnight at room temperature and phosphopeptides enriched by TiO2 beads. The enriched peptides were desalted, washed and eluted on StageTips with 2 layers of SDB-RPS material with elution buffer (80% Acetonitrile and 5% NH4OH). The eluted peptides were vacuum centrifuged until dryness and reconstituted in 2% ACN /0.1% TFA. All the samples were stored in -20ºC until measurement."],"repository":["Pride"],"quantification_method":["Spectrum counting","Label free"],"modification":["phosphorylated residue"],"data_protocol":["Mass spectrometric raw files were processed using the Andromeda search engine integrated into Maxquant environment (1.5.5.2 version). The MS/MS spectra were matched against the mouse (UniProt FASTA 2015_08) database with an FDR < 0.01 at the level of proteins, peptides and modifications. The search included fixed modification for carbamidomethyl and in the variable modifications table phosphoSTY was added additionally for the phosphorylated peptide search to the default settings. Peptides with at least seven amino acids were considered for identification. Maximum two missed cleavages were allowed for protease digestion. Match between run was enabled with the matching window of 1 min to transfer peptide identification to across runs based on normalized retention time and high mass accuracy."],"omics_type":["Proteomics"],"labhead":["Prof.Matthias Mann"],"instrument_platform":["Q Exactive"],"submission_type":["PARTIAL"],"labhead_affiliation":["MaxPlanck Insitute of Biochemistry, Munich,Germany"],"species":["Homo Sapiens (human)","Mus Musculus (mouse)"],"publication":["33239784 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 10.1038/s41586-020-2968-3"],"submitter_mail":["oroshi@biochem.mpg.de"],"submitter_affiliation":["Proteomics"],"submitter_country":["Germany"],"pubmed_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."],"pubmed_title":["Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms."],"pubmed_authors":["Jayavelu Ashok Kumar AK, Schnöder Tina M TM, Perner Florian F, Herzog Carolin C, Meiler Arno A, Krishnamoorthy Gurumoorthy G, Huber Nicolas N, Mohr Juliane J, Edelmann-Stephan Bärbel B, Austin Rebecca R, Brandt Sabine S, Palandri Francesca F, Schröder Nicolas N, Isermann Berend B, Edlich Frank F, Sinha Amit U AU, Ungelenk Martin M, Hübner Christian A CA, Zeiser Robert R, Rahmig Susann S, Waskow Claudia C, Coldham Iain I, Ernst Thomas T, Hochhaus Andreas A, Jilg Stefanie S, Jost Philipp J PJ, Mullally Ann A, Bullinger Lars L, Mertens Peter R PR, Lane Steven W SW, Mann Matthias M, Heidel Florian H FH"],"pubmed_abstract_synonyms":["Ribonucleic, DmErk, extracellular signal-regulated kinase activity, pp44mapk, Tyro5, FON1, via spliceosome, regulation of cellular transcription, FLORAL ORGAN NUMBER 1, p38a, Mutations, dmTAF[[II]]230, LeMPK3, HOP, Hop, Programmed, p44mpk, Dp38, 4, Kinase, SAPK2, SEM, Sem, Non Polyadenylated, p38A, chronic myeloproliferative disorder, MAP-k, mYB-1a, Tum-1, organa haemopoietica, TFIID TAF250, pp42, haemopoietic system, cel, EK5, Bdr, Dsor2, U, proteins, sem, SNAP-25, endocrine, Nsep1, Intrinsic Pathway Apoptosis, chronic myeloproliferative disorders, Homo sapiens disease, ATP Phosphotransferases, single organism signaling, DmMPK2, ERK-A, dTAF[[II]]230, dpERK, dpErk, JAK Inhibitors, myeloproliferative tumor, ERK-1, ERK-2, TAF200, DmMAPK, Receptor Agonists, PMK-2, dp-ERK, PMK-1, PMK-3, signaling (initiator) caspase activity, induction of apoptosis, myeloproliferative disorder, pMAPK, pMapK, GENA70, regulation of transcription, Ribonucleic acids, D-MPK2, Caspase-Dependent, d-jak, Acid, DmelCG5475, DmHD-160, DmERKA, rl/MAPK, INSDC_feature:gene, l(2)41Ac, Mtap2k, chronic myeloproliferative neoplasm, human, mRNA maturation, C78273, Intrinsic Pathway Apoptoses, CT34260, dpERk, Taf250, HD-160, SAPK, CSDB, Extrinsic Pathway, Mouse, CG1594, TAF230, 9030612K14Rik, FLORAL DEFECTIVE 10, p44erk1, D-p38 MAPK, JTK10., Hop1, 12559, SUPERMAN, apoptotic programmed cell death, splicing, activation of apoptosis, EK2-1, Hormone, myeloproliferative neoplasms, AA407128, JAK Kinases, hematolymphoid system, dMPK2, Gene Products, disease or disorder, Prkm1, Prkm3, protein-tyrosine kinase activity, ERK, Erk, PRKM1, PRKM3, PRKM2, dTAF[[II]]250, p38Ka, cell, PCBC, man, erk, regulation of gene-specific transcription, dTAF250, Cbfa, L4, Classic Apoptosis, execution phase of apoptotic process, NSEP1, rll, Intron, STK26, p38-2, myelin basic protein kinase activity, Apoptosis, disease remission, Dp38a, RNA, JAK Inhibitor, cell suicide, DRT, Esrk1, Proteins, apoptotic cell death, disorders, stress-activated kinase activity, MAP-2 kinase activity, RNS, Synaptosomal-associated 25 kDa protein, BG:DS00004.13, AMH, Cell, chronic, dTAF230, Sequences, 1700102N10Rik, Cytokine, stress-activated protein kinase activity, mapk2, mapk1, TAF[[II]]250/230, condition, NCI CTEP SDC Chronic Myeloproliferative Disease Sub-Category Terminology, Taf[[II]]250, CG12559, apoptosis, C79409, P42MAPK, dpERK1, DNA-templated, Ribonucleic Acid, signalling, Blutbildungssystem, Classic Apoptoses, ageing, Gene Proteins, extracellular, AU018647, signalling process, dpMAPK, apoptotic program, Tum, commitment to apoptosis, JAK, Jak, l(1)10Be, p44mapk, myeloproliferative neoplasm, SAP kinase activity, AI504024, Janus Kinase Inhibitor, Mpk2, p42mapk, jak, D-p38, JTK10, type I programmed cell death, p38 alpha, SR2-1, P44ERK1, l(1)L4, diseases, Yb1, Extrinsic Pathway Apoptoses, Kinase Inhibitors, MIF, SUP, Inhibitors, diseases and disorders, mitogen-activated protein kinase activity, MIS, mpk2, mpk1, RNA Gene Products, hematological system, Kinase Inhibitor, DmelCG1594, YB-1, human disease, Erk/Map kinase, YB1, Hormone Receptor, DERK-A, E(sina)7, Super protein, Rl, sp, DNA-dependent, MP kinase activity, DERK, BP-8, Dmp38a, Classic, signaling process, Janus kinase activity, Classical Apoptosis, MBP kinase II activity, ATP - protein phosphotransferase (MAPKK-activated) activity, transcriptional control, dERK, house mouse, CG5475, hemopoietic system, ATP, cellular suicide, MNK1, Mnk1, MAP kinase 2 activity, Caspase-Dependent Apoptosis, ribose nucleic acid, Mapk, Intervening Sequences, ribonucleic acids, mouse, Erk1, ERK1, ERK2, mapk1a, Janus, Erk2, TAFII-250, TAF250/230, results, D-P38a, D-p38a, THCYT3, TAFII250, p41mapk, Intrinsic Pathway, MapK, mapk1b, MAPK, Extrinsic Pathway Apoptosis, Ribonukleinsaeure, Diseases, EF1A, pentosenucleic acids, P38, erk2, mapk, Transphosphorylases, ERKa, BcDNA:RE08694, l(2R)EMS45-39, mice, CAPB, Janus Kinase, DmelCG12559, p38, Cell Death, Byb1, CG17603, TAF[[II]], Intervening, DpErk, DpERK, ErkA, disease, ERKA, HUMKER1A, induction of apoptosis by p53, SR3-5, p41, p40, msvl, DBPB, P44MAPK, Ef1a, p44, Inhibitor, Classical, Apoptoses, pERK, dbpB, MPD, other disease, biological signaling, d230, nuclear mRNA cis splicing, human being, MPN, GroupII, caspase-dependent programmed cell death, chronic myeloproliferative disease, Gene, Caspase Dependent Apoptosis, dTAFII250, NSEP-1, EfW1, protein amino acid phosphorylation, dp38a, Hek5, HS44KDAP, dmTAF1, Taf230, Dbpb, Anti-Muellerian hormone, C81284, CSDA2, p42-MAPK, Type I, Agonists, MSY1, Msy1, Phosphotransferase, TAF250, Taf200, hormones, xp42, haematopoietic system, Taf1p, Hormone Receptor Agonists, Transphosphorylase, apoptosis activator activity, Maintenances, p42 mitogen-activated protein kinase activity, l(1)hop, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, non-neoplastic, Non-Polyadenylated RNA, Mif1, Erk-1, via U2-type spliceosome, disorder, DmERK-A, TAF, programmed cell death by apoptosis, ert1, TAF[[II]]250, DMPK2, prkm2, CT39192, prkm1, l(3)84Ab, medical condition, Muellerian-inhibiting substance, Phosphotransferases, p38delta, Fd17, MDR-NF1, Intervening Sequence, Mus, Sequence, yeast nucleic acid, group 2, p230, Programmed Cell Death, Protein, MBP kinase I activity, TFIID, Xp42, CMPD, apoptosis signaling, haematological system, ribonucleic acid, TAF[[II]]230, Kinases, mitogen activated kinase activity, Non Polyadenylated RNA, Su(Raf)2B, Non-Polyadenylated, FLO10, EY2-2, TAF[II]250, MAPK2, MAPK1, HERP, dp38, Protein Gene Products, Dm JAK, D-ERK, DmelCG17603, Ert2, ERT1, ERT2, EPHT3, p44-MAPK, p44-ERK1, l(1)G18, myeloproliferative tumour, MAP kinase 1 activity, TAF1"],"data_synonyms":["Bru, DYRK1, Raw, Aminokarbonsaeure, Aminosaeure, Proteins, mouse, Aminocarbonsaeure, Dmel_CG7826, FBN, 1.5.5.2, Amino acid, Gene, Search, alpha-amino acids, alpha-amino acid, large mass, Kidney and liver proline oxidase 1, Peptide, alpha-amino carboxylic acids, Engine, CG7826, ACMICD, Impact, Environmental, polypeptide, peptide, Polypeptides, peptido, ClvPrd, Dm1, Mus, ECTOL1, Protein, Gene Products, CG7835, CG42273, Impacts, MFS1, Min, Del(8)44H, Dyrk1, Environmental Impacts, Proline oxidase, Proline oxidase-like protein, WMS, Dmel_CG7835, WMS2, Data Base, DmelCG42273, Mnb, MNB, Svc, AU020952, Amino Acid, Acid, Search Engines, Col4a-1, amino acids, peptides, Amino acids, mice, CC1, MmPOX1, min, mAPC, proteins, MASS, Amino, AW124434, ME-IV, OCTD, Protein Gene Products, AI047805, Environmental Impact, Gene Proteins, Table, Probable proline oxidase 2, high mass., SSKS, Environments, Peptid, peptidos, Mouse, Acids, Polypeptide, house mouse, variable, GPHYSD2, SGS, PO"],"name_synonyms":["AI504024, DmErk, extracellular signal-regulated kinase activity, pp44mapk, Tyro5, Mpk2, via spliceosome, p42mapk, D-p38, Tumor, JTK10, p38 alpha, p38a, SR2-1, LeMPK3, P44ERK1, Yb1, p44mpk, Dp38, mitogen-activated protein kinase activity, SAPK2, mpk2, SEM, Sem, mpk1, p38A, MAP-k, mYB-1a, YB-1, Erk/Map kinase, YB1, pp42, EK5, DERK-A, Dsor2, E(sina)7, sem, Rl, 2410048M24Rik, Nsep1, MP kinase activity, DERK, BP-8, Dmp38a, signaling process, MBP kinase II activity, ATP - protein phosphotransferase (MAPKK-activated) activity, Malignancies, dERK, CG5475, DmMPK2, single organism signaling, Tumors, ERK-A, MNK1, Mnk1, MAP kinase 2 activity, dpERK, dpErk, Mapk, ERK-1, ERK-2, Erk1, ERK1, ERK2, mapk1a, DmMAPK, Erk2, PMK-2, dp-ERK, PMK-1, D-P38a, PMK-3, D-p38a, THCYT3, Benign, p41mapk, MapK, mapk1b, MAPK, EF1A, pMAPK, pMapK, P38, D-MPK2, erk2, mapk, DmelCG5475, ERKa, DmERKA, rl/MAPK, BcDNA:RE08694, l(2R)EMS45-39, CAPB, DmelCG12559, Benign Neoplasms, p38, l(2)41Ac, Byb1, Mtap2k, Malignant Neoplasms, C78273, DpErk, DpERK, ErkA, ERKA, HUMKER1A, CT34260, dpERk, p41, p40, DBPB, SAPK, P44MAPK, Ef1a, CSDB, p44, pERK, dbpB, 9030612K14Rik, p44erk1, D-p38 MAPK, biological signaling, nuclear mRNA cis splicing, GroupII, Neoplasms, Benign Neoplasm, 12559, NSEP-1, splicing, Malignant, EK2-1, dp38a, Hek5, HS44KDAP, AA407128, dMPK2, Dbpb, Prkm1, C81284, CSDA2, Prkm3, p42-MAPK, MSY1, Msy1, ERK, Erk, PRKM1, PRKM3, PRKM2, p38Ka, Malignancy, xp42, PCBC, p42 mitogen-activated protein kinase activity, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, erk, Neoplasias, Erk-1, via U2-type spliceosome, Cbfa, NSEP1, rll, DmERK-A, STK26, p38-2, myelin basic protein kinase activity, Cancer, signalling., Dp38a, ert1, DRT, Malignant Neoplasm, Esrk1, DMPK2, stress-activated kinase activity, prkm2, CT39192, prkm1, MAP-2 kinase activity, p38delta, MDR-NF1, Fd17, 1700102N10Rik, group 2, stress-activated protein kinase activity, mapk2, mapk1, Neoplasm, MBP kinase I activity, Xp42, CG12559, mitogen activated kinase activity, C79409, Su(Raf)2B, P42MAPK, dpERK1, EY2-2, Cancers, MAPK2, MAPK1, dp38, AU018647, D-ERK, signalling process, dpMAPK, Ert2, ERT1, ERT2, EPHT3, p44-MAPK, p44-ERK1, p44mapk, Neoplasia, SAP kinase activity, MAP kinase 1 activity"],"pubmed_title_synonyms":["AI504024, mYB-1a, YB-1, nuclear mRNA cis splicing, Malignant Neoplasm, YB1, Malignancy, C79409, Neoplasms, Benign Neoplasm, via spliceosome, Benign Neoplasms, Cancers, NSEP-1, Byb1, Tumor, JTK10, splicing, Malignant, Nsep1, Neoplasias, via U2-type spliceosome, THCYT3, Cbfa, MDR-NF1, Fd17, 1700102N10Rik, BP-8, Benign, Yb1, DBPB, Dbpb, NSEP1, Neoplasm, EF1A, Ef1a, CSDB, C81284, CSDA2, Malignancies, MSY1, Msy1, Neoplasia, dbpB, Cancer, Tumors, Malignant Neoplasms."],"sample_synonyms":["IL1BC, Sleep Apnea Syndromes, sleep apnea syndrome, MeCN, NCMe, hypersomnia with periodic respiration, fond, CASP-1, SDB, CG7788, crice, CycEI, 10X, HCHWA, Bca, 2-Propanone, peptide, Polypeptides, Sleep Disordered Breathing, Ccne, peptido, diseases, BANF, CH3-C#N, SEC, sleep apneas, diseases and disorders, AGM4, mixed central and obstructive sleep apnea, Il1bc, 10x, bca, human disease, C79325, 10x single cell library construction, peptides, 2610036I19Rik, sec, sleep, hypopnea, 2610510L13Rik, proteins, IL-1BC, genetic, fSAP152, Sleep-Disordered Breathing, ICE, ACN, Acn, breathing-related sleep disorder, Homo sapiens disease, Sleep, Lyw-57, hypopneas, Mixed Sleep Apneas, Hypopneas, Caspase-1 subunit p10, ice, iCE, drice, familial, Sleep Hypopnea, 10x sequencing, mixed central and obstructive, mixed sleep apnea, Cyc E, br37, Apnea Syndromes, DmelCG7788, hereditary cerebral hemorrhage with amyloidosis - Dutch type, SLP65, Ly-57, Hypersomnia with Periodic Respiration, BG:DS07108.3, drIce, drICE, sleep hypopnea, l(2)05206, SLP-65, BASH, LY57, P45, Mixed Sleep Apnea, study protocol, beta Trypsin, apnea syndromes, disease, breathing, l35Dd, Drice, p45, Polypeptide, mixed sleep Apneas, sleep disordered breathing, methyl cyanide, DRICE, Mixed Central and Obstructive Sleep Apnea, sleep-disordered, mKIAA0670., other disease, apnea syndrome, dutch hereditary cerebral amyloid angiopathy, cycline, DrIce, DrICE, DmcyclinE, Apnea, Gene, cycE, ACINUS, l(2)br37, sleep apnea, CYCLE, Buffer, Sleep Apneas, cdi7, sleep hypopneas, method, Apnea Syndrome, Sleep Apnea, cyclinE, Ly57, method used in an experiment, Cdi7, CDI7, Gene Products, disease or disorder, apneas, T6K12_14, CYCE, Acinus, DmelCG3938, CyclE, Selb, PCE-2, beta-Trypsin, 3938, DmcycE, non-neoplastic, acinusL, l(2)k05007, dm-cycE, Sleep Hypopneas, Caspase-1 subunit p20, acinusS, apnea, disorder, peptidos, 10X sequencing, TCEP, BLNK-S, Sleep Apnea Syndrome, 1-(14)C-labeled, 3H-labeled, caspase 3, TSH1, Proteins, disorders, sleep-disordered breathing, medical condition, CE-2, NY-CO-33, acetonitrile, buffer, Hypopnea, Peptide, CAA, polypeptide, secret agent, l(2)k02514, Phosphopeptide, DmCycE, Temperatures, Protein, Apneas, condition, Mixed, CES2A1, CyeE, Vacuums, SDCCAG33, Breathing, ACETONITRILE, cyanomethane, T6K12.14, l(2)k02602, mixed, l(2)35Dd, Tripcellim, cerebral amyloid angiopathy, Sleep-Disordered, IL-1 beta-converting enzyme, ethanenitrile, Interleukin-1 beta-converting enzyme, plan specification, Interleukin-1 beta convertase, Protein Gene Products, D-CycE, Gene Proteins, Trypure, 3.4.22.36, Peptid, 10x Genomics, SCH, CG3938, hereditary cerebral haemorrhage with amyloidosis - Dutch type, Mixed Central and Obstructive"],"description_synonyms":["Ribonucleic, DmErk, extracellular signal-regulated kinase activity, pp44mapk, Materials, Tyro5, via spliceosome, regulation of cellular transcription, growth and development, p38a, Mutations, dmTAF[[II]]230, LeMPK3, HOP, Hop, Biological, Programmed, p44mpk, Dp38, 4, Kinase, SAPK2, SEM, Sem, Non Polyadenylated, p38A, chronic myeloproliferative disorder, MAP-k, Senescence, mYB-1a, Tum-1, organa haemopoietica, TFIID TAF250, pp42, haemopoietic system, cel, EK5, Dsor2, U, proteins, sem, endocrine, Nsep1, Biological Aging, Intrinsic Pathway Apoptosis, chronic myeloproliferative disorders, Homo sapiens disease, ATP Phosphotransferases, single organism signaling, DmMPK2, ERK-A, dTAF[[II]]230, dpERK, dpErk, myeloproliferative tumor, ERK-1, ERK-2, TAF200, DmMAPK, PMK-2, dp-ERK, PMK-1, PMK-3, signaling (initiator) caspase activity, induction of apoptosis, myeloproliferative disorder, pMAPK, pMapK, regulation of transcription, Ribonucleic acids, D-MPK2, Caspase-Dependent, d-jak, Acid, DmelCG5475, DmHD-160, Hematopoietic, DmERKA, rl/MAPK, l(2)41Ac, Mtap2k, chronic myeloproliferative neoplasm, human, mRNA maturation, C78273, Intrinsic Pathway Apoptoses, CT34260, Hematopoietic Systems, dpERk, Taf250, HD-160, Material, hemopoietic tissue, SAPK, CSDB, Extrinsic Pathway, CG1594, TAF230, 9030612K14Rik, p44erk1, D-p38 MAPK, Hop1, 12559, apoptotic programmed cell death, splicing, activation of apoptosis, EK2-1, myeloproliferative neoplasms, AA407128, JAK Kinases, hematolymphoid system, dMPK2, Gene Products, disease or disorder, Prkm1, Prkm3, Cell., protein-tyrosine kinase activity, ERK, Erk, PRKM1, PRKM3, PRKM2, dTAF[[II]]250, p38Ka, cell, PCBC, man, erk, regulation of gene-specific transcription, dTAF250, Cbfa, L4, Classic Apoptosis, execution phase of apoptotic process, NSEP1, rll, STK26, p38-2, myelin basic protein kinase activity, Apoptosis, disease remission, inhibitors, Dp38a, RNA, cell suicide, DRT, Esrk1, Proteins, apoptotic cell death, disorders, stress-activated kinase activity, MAP-2 kinase activity, RNS, BG:DS00004.13, AMH, Cell, chronic, dTAF230, 1700102N10Rik, Cytokine, stress-activated protein kinase activity, mapk2, mapk1, TAF[[II]]250/230, condition, NCI CTEP SDC Chronic Myeloproliferative Disease Sub-Category Terminology, Taf[[II]]250, CG12559, apoptosis, C79409, P42MAPK, dpERK1, postnatal growth, DNA-templated, Ribonucleic Acid, signalling, Blutbildungssystem, Classic Apoptoses, Gene Proteins, extracellular, AU018647, signalling process, dpMAPK, apoptotic program, Tum, commitment to apoptosis, JAK, Jak, l(1)10Be, p44mapk, myeloproliferative neoplasm, SAP kinase activity, AI504024, Mpk2, postnatal development, p42mapk, jak, Aging, D-p38, JTK10, type I programmed cell death, p38 alpha, hematopoietic tissue, SR2-1, P44ERK1, l(1)L4, diseases, Yb1, Extrinsic Pathway Apoptoses, MIF, diseases and disorders, mitogen-activated protein kinase activity, MIS, mpk2, mpk1, RNA Gene Products, hematological system, DmelCG1594, YB-1, human disease, Erk/Map kinase, YB1, DERK-A, E(sina)7, Rl, DNA-dependent, MP kinase activity, DERK, BP-8, Dmp38a, Classic, signaling process, Janus kinase activity, Classical Apoptosis, MBP kinase II activity, ATP - protein phosphotransferase (MAPKK-activated) activity, transcriptional control, dERK, CG5475, hemopoietic system, ATP, cellular suicide, MNK1, Mnk1, MAP kinase 2 activity, Caspase-Dependent Apoptosis, ribose nucleic acid, Mapk, ribonucleic acids, incomplete, Erk1, ERK1, ERK2, mapk1a, Janus, Erk2, TAFII-250, TAF250/230, results, D-P38a, abolished, D-p38a, THCYT3, TAFII250, p41mapk, INSDC_feature:intron, Intrinsic Pathway, MapK, mapk1b, MAPK, Extrinsic Pathway Apoptosis, Ribonukleinsaeure, Diseases, EF1A, Genetic Materials, pentosenucleic acids, P38, erk2, Genetic Material, mapk, Transphosphorylases, ERKa, BcDNA:RE08694, growth pattern, l(2R)EMS45-39, non-developmental growth, System, CAPB, Janus Kinase, DmelCG12559, p38, Cell Death, Byb1, CG17603, TAF[[II]], DpErk, DpERK, ErkA, disease, ERKA, HUMKER1A, induction of apoptosis by p53, SR3-5, p41, p40, msvl, DBPB, P44MAPK, Ef1a, p44, Cistron, Classical, Proteomes, Apoptoses, pERK, dbpB, MPD, other disease, biological signaling, d230, nuclear mRNA cis splicing, human being, MPN, GroupII, caspase-dependent programmed cell death, Gene, chronic myeloproliferative disease, Caspase Dependent Apoptosis, dTAFII250, NSEP-1, EfW1, protein amino acid phosphorylation, dp38a, Hek5, HS44KDAP, dmTAF1, Taf230, Dbpb, Anti-Muellerian hormone, C81284, CSDA2, p42-MAPK, Type I, MSY1, Msy1, Phosphotransferase, TAF250, Taf200, hormones, Genetic, xp42, haematopoietic system, inhibiteur, Taf1p, Transphosphorylase, apoptosis activator activity, Maintenances, p42 mitogen-activated protein kinase activity, l(1)hop, CG18732, ATP:protein phosphotransferase (MAPKK-activated) activity, non-neoplastic, Non-Polyadenylated RNA, Erk-1, via U2-type spliceosome, inhibidor, disorder, DmERK-A, TAF, programmed cell death by apoptosis, ert1, TAF[[II]]250, DMPK2, prkm2, CT39192, prkm1, total expressed protein, inhibitor, l(3)84Ab, medical condition, Muellerian-inhibiting substance, Cistrons, Phosphotransferases, development, p38delta, Fd17, MDR-NF1, yeast nucleic acid, group 2, p230, Programmed Cell Death, Protein, MBP kinase I activity, TFIID, Xp42, CMPD, apoptosis signaling, haematological system, ribonucleic acid, TAF[[II]]230, Kinases, mitogen activated kinase activity, Non Polyadenylated RNA, Su(Raf)2B, Non-Polyadenylated, haematopoietic tissue, EY2-2, TAF[II]250, MAPK2, MAPK1, dp38, Protein Gene Products, Dm JAK, D-ERK, DmelCG17603, Ert2, ERT1, ERT2, EPHT3, p44-MAPK, p44-ERK1, l(1)G18, growth, myeloproliferative tumour, MAP kinase 1 activity, Intrinsic, TAF1"],"additional_accession":[]},"is_claimable":false,"name":"Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling","description":"Janus kinases (Jak) mediate cytokine, hormone and growth factor responses in hematopoietic cells. Jak2 is one of the most frequently mutated genes in the aging hematopoietic system and in hematopoietic cancers. Mutations in Jak constitutively activate downstream signaling and are drivers of myeloproliferative neoplasms (MPN). In clinical use, Jak-inhibitors have incomplete effects on overall disease burden of Jak2 mutated clones, prompting us to investigate the mechanism underlying disease persistence. By in-depth phospho-proteome profiling we here identify proteins involved in mRNA processing as targets of mutant Jak2. Inactivation of the post-translationally modified Jak2-target Ybx1 sensitizes Jak-inhibitor persistent cells to apoptosis and results in RNA mis-splicing, retained intron enrichment and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signaling. In combination with pharmacological Jak-inhibition it induces apoptosis in Jak2-dependent murine and primary human cells, leading to in vivo regression of the malignant clones and inducing remission. This identifies and validates a novel cell-intrinsic mechanism how differential protein phosphorylation results in splicing-dependent alterations of Jak2-ERK-signaling and the maintenance of Jak2V617F malignant clones. Therapeutic targeting of Ybx1 dependent ERK-signaling in combination with Jak2-inhibition may eradicate Jak2-mutated 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