RT Journal Article
T1 Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia
A1 Morales, María Luz
A1 García Vicente, Roberto
A1 Rodrígue García, Alba
A1 Reyes Palomares, Armando Adolfo
A1 Vincelle Nieto, África
A1 Álvarez, Noemí
A1 Ortiz Ruiz, Alejandra
A1 Garrido García, Vanesa
A1 Giménez, Alicia
A1 Carreño Tarragona, Gonzalo
A1 Sánchez, Ricardo
A1 Ayala Díaz, Rosa María
A1 Martínez López, Joaquín
A1 Linares Gómez, María
AB 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.
SN 0887-6924
SN 1476-5551
YR 2023
FD 2023-07-08
LK https://hdl.handle.net/20.500.14352/101903
UL https://hdl.handle.net/20.500.14352/101903
LA eng
NO Morales, M. L., García Vicente, R., Rodríguez García, A. et al. «Posttranslational Splicing Modifications as a Key Mechanism in Cytarabine Resistance in Acute Myeloid Leukemia». Leukemia, vol. 37, n.o 8, agosto de 2023, pp. 1649-59. DOI.org (Crossref), https://doi.org/10.1038/s41375-023-01963-4.
DS Docta Complutense
RD 11 abr 2025