Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia.

ABSTRACT: 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

SUBMITTER: Morales ML 

PROVIDER: S-EPMC10400425 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature