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Disease
Symptom
Drug
Enzyme
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Target Concepts:
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Query: UMLS:C0026986 (
myelodysplastic syndrome
)
14,926
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
SF3B1
,
SRSF2
, and
U2AF1
are the most frequently mutated splicing factor genes in the
myelodysplastic syndromes
(
MDS
). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant
MDS
. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34
+
cells of 84 patients with
MDS
. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in
MDS
. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in
MDS
, whereas several others have not been previously associated with
MDS
, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in
MDS
and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the
MDS
-affected lineages in splicing factor mutant
MDS
. Functional studies demonstrated that knockdown of the mitosis regulators
SEPT2
and
AKAP8
,
aberrantly spliced target genes of
SF3B1
and
SRSF2
mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the
MDS
phenotype and provides novel insights into disease pathophysiology.
...
PMID:Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations. 3023 52
