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RNA splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling

ABSTRACT: RNA splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling

PROVIDER: PRJNA611763 | ENA |

REPOSITORIES: ENA

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Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling

Project 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 cells.

2020-08-20 | PXD006921 | Pride

Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling persistent clones in Jak2-mutated neoplasms

Project description:Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling persistent clones in Jak2-mutated neoplasms

| PRJNA644892 | ENA

Splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling persistent clones in Jak2-mutated neoplasms

Project description:Inactivation of Ybx1 results in RNA mis-splicing, retained intron enrichment and disruption of the transcriptional and post-translational control of extracellular signal-regulated kinase (ERK) signaling

2020-07-08 | GSE154025 | GEO

Splicing factor Ybx1 mediates persistence of Jak2-mutated neoplasms

Project 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 cells.

2018-12-07 | GSE123417 | GEO

RNA splicing factor Ybx1 maintains persistent Jak2-mutated neoplasms via Mknk1-ERK-signaling

Project description:Measurement of DNA-binding of YBX1 in the HEL cell line (JAK2V617F mutated human cells)

2020-03-11 | GSE146717 | GEO

Splicing factor Ybx1 mediates persistence of Jak2-mutated neoplasms

Project description:Splicing factor Ybx1 mediates persistence of Jak2-mutated neoplasms

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Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predispose to myeloproliferative neoplasms

Project description:Genome-wide association study of JAK2 V617F negative myeloproliferative neoplasms consisting of 524 cases at stage 1

2015-02-20 | E-MTAB-3340 | biostudies-arrayexpress

Chip-chip from HCT116 cells with YBX1

Project description:YBX1 is a multifunctional protein involved in the control of transcription and translation. We identified YBX1 as an target of MEK/ERK signaling in colorectal cancer cell lines. We performed a ChIP-chip analysis of HCT116 cells to identify new potential target genes of YBX1. Comparison of input DNA fragments with fragments coprecipitated with YBX1 in HCT116 cells.

2010-10-09 | E-GEOD-18337 | biostudies-arrayexpress

Talarmain2022- Model of JAK2/TET2/HOXA9 in myeloproliferative neoplasms

Project description:Model describing how HOXA9 may control the evolution of myeloproliferative neoplasms by integrating the orders of JAK2 and TET2 mutation

2023-03-17 | MODEL2212110001 | BioModels

Chip-chip from HCT116 cells with YBX1

2010-10-09 | GSE18337 | GEO

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