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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE154025 | GEO | 2020/07/08

REPOSITORIES: GEO

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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

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

| PRJNA611763 | ENA

Splicing factor Ybx1 mediates persistence of Jak2-mutated neoplasms

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

| PRJNA508726 | ENA

YBX1 HITS-CLIP

Project description:In order to identify YBX1 binding sites on endogenous RNA, we performed HITS-CLIP on endogenous YBX1 We used a previously published method to perform HITS-CLIP on endogenous YBX1 (Licatalosi D, et al. 2008, Nature 456:464-U22)

2015-05-08 | E-GEOD-63604 | biostudies-arrayexpress

YBX1 small-RNA HITS-CLIP

Project description:In order to identify YBX1 binding sites on tRNA fragments, we performed small-RNA HITS-CLIP on endogenous YBX1 We used a previously published method to perform HITS-CLIP on endogenous YBX1 (Chi SW, et al. 2009, Nature 460:479)

2015-05-08 | E-GEOD-63597 | 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

YBX1-dependent hypoxia-induced modulation of gene expression

Project description:In order to identify YBX1-dependent targets that are modulated under hypoxic conditions, we used control and YBX1 knockdown cells grown under normoxia and hypoxia to profile gene expression levels. Control and YBX1-knockdown cells were grown and profiled under hypoxia and normoxia to identify YBX1-dependent hypoxia-induced target transcripts.

2015-05-08 | E-GEOD-63562 | biostudies-arrayexpress

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