Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia.
Maria Luz MoralesRoberto García-VicenteAlba Rodríguez-GarcíaArmando Reyes-PalomaresÁfrica Vincelle-NietoNoemí ÁlvarezAlejandra Ortiz-RuizVanesa Garrido-GarcíaAlicia GiménezGonzalo Carreno-TarragonaRicardo SanchezRosa AyalaJoaquin Martinez LopezMaría LinaresPublished in: Leukemia (2023)
Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and serine-arginine-rich (SR) proteins phosphorylation were altered during cytarabine resistance. Moreover, phosphorylation of SR proteins at diagnosis were significantly lower in responder than non-responder patients, pointing to their utility to predict response. These changes correlated with altered transcriptomic profiles of SR protein target genes. Notably, splicing inhibitors were therapeutically effective in treating sensitive and resistant AML cells as monotherapy or combination with other approved drugs. H3B-8800 and venetoclax combination showed the best efficacy in vitro, demonstrating synergistic effects in patient samples and no toxicity in healthy hematopoietic progenitors. Our results establish that RNA splicing inhibition, alone or combined with venetoclax, could be useful for the treatment of newly diagnosed or relapsed/refractory AML.
Keyphrases
- acute myeloid leukemia
- newly diagnosed
- rna seq
- end stage renal disease
- single cell
- chronic kidney disease
- ejection fraction
- high dose
- peritoneal dialysis
- allogeneic hematopoietic stem cell transplantation
- nitric oxide
- induced apoptosis
- protein kinase
- bone marrow
- gene expression
- prognostic factors
- signaling pathway
- drug delivery
- genome wide
- study protocol
- small molecule
- open label
- binding protein
- hodgkin lymphoma
- bioinformatics analysis