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Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms

ABSTRACT: Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms

PROVIDER: PRJEB41023 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR4776870.fastq.gz	Fastqsanger.gz
	ERR4776880_1.fastq.gz	Fastqsanger.gz
	ERR4776880_2.fastq.gz	Fastqsanger.gz
	ERR4776871.fastq.gz	Fastqsanger.gz
	ERR4776881_1.fastq.gz	Fastqsanger.gz

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Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms

Project description:We characterized the functions of the understudied LUC7-like family of splicing factors in human cells using seCLIP-seq, RBP knockdown followed by RNA-seq, and Co-IP mass spectrometry.

2021-04-14 | E-MTAB-9709 | biostudies-arrayexpress

Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms

Project description:We chracaterized the functions of the understudied LUC7-like family of splicing factors in human cells using seCLIP-seq, RBP knockdown followed by RNA-seq, and Co-IP mass spectrometry.

2021-09-09 | PXD022152 | Pride

Functional analyses of human LUC7-like proteins involved in splicing regulation and myeloid neoplasms.

Project description:Vertebrates have evolved three paralogs, termed LUC7L, LUC7L2, and LUC7L3, of the essential yeast U1 small nuclear RNA (snRNA)-associated splicing factor Luc7p. We investigated the mechanistic and regulatory functions of these putative splicing factors, of which one (LUC7L2) is mutated or deleted in myeloid neoplasms. Protein interaction data show that all three proteins bind similar core but distinct regulatory splicing factors, probably mediated through their divergent arginine-serine-rich domains, which are not present in Luc7p. Knockdown of each factor reveals mostly unique sets of significantly dysregulated alternative splicing events dependent on their binding locations, which are largely non-overlapping. Notably, knockdown of LUC7L2 alone significantly upregulates the expression of multiple spliceosomal factors and downregulates glycolysis genes, possibly contributing to disease pathogenesis. RNA binding studies reveal that LUC7L2 and LUC7L3 crosslink to weak 5' splice sites and to the 5' end of U1 snRNA, establishing an evolutionarily conserved role in 5' splice site selection.

| S-EPMC8078730 | biostudies-literature

Inherited and somatic defects in DDX41 in myeloid neoplasms

Project description:Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-Box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases lead to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples.

2015-04-01 | E-GEOD-66668 | biostudies-arrayexpress

Splicing factor Ybx1 mediates persistence of Jak2-mutated neoplasms

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

| PRJNA508726 | ENA

Inherited and somatic defects in DDX41 in myeloid neoplasms

2015-04-01 | GSE66668 | GEO

Mutations in the splicing factor SF3B1 are linked to frequent emergence of HLA-DRlow/neg monocytes in lower-risk myelodysplastic neoplasms

Project description:Recurrent mutations in splicing factors, in particular the splicing factor 3B subunit 1 (SF3B1), are commonly seen in lower-risk (LR) myelodysplastic neoplasms (MDS) and result in various aberrantly spliced transcripts. The cell type-specific changes and their contribution to immune dysregulation in MDS remain vaguely understood. In this study, we performed RNA sequencing on classical monocytes isolated from patients with an isolated SF3B1K700E hotspot mutation. Our analysis revealed downregulated expression of genes involved in inflammatory cytokine signaling, as well as differential mRNA splicing of several genes involved in the regulation of the defense response and cytokine signaling, mRNA metabolism, apoptotic signaling, and mitotic cell cycle.

2024-04-18 | GSE236535 | GEO

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 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

Integrative RNA-omics discovers GNAS alternative splicing as a phenotypic driver of splicing factor mutant neoplasms

Project description:Mutations in splicing factors (SFs) are the predominant class of mutations in myelodysplastic syndrome (MDS), but convergent downstream disease drivers remain elusive. To identify common direct targets of mis-splicing by mutant U2AF1 and SRSF2, we performed RNA-Seq and eCLIP in human hematopoietic stem/progenitor cells (HSPCs) derived from isogenic induced pluripotent stem cell (iPSC) models. Integrative analyses of alternative splicing and differential binding converged on a long isoform of GNAS (GNAS-L), promoted by both mutant factors. MDS population genetics, functional and biochemical analyses support that GNAS-L is a driver of MDS and encodes a hyperactive long form of the stimulatory G protein alpha subunit, Gas-L, that activates ERK/MAPK signaling. SF-mutant MDS cells have activated ERK signaling and consequently are sensitive to MEK inhibitors. Our findings highlight an unexpected and unifying mechanism by which SF mutations drive oncogenesis with potential therapeutic implications for MDS and other SF-mutant neoplasms.

2021-09-17 | GSE164666 | GEO

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