2. Academic Validation
  3. Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia

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

  • Leukemia. 2023 Jul 8. doi: 10.1038/s41375-023-01963-4.
María Luz Morales # 1,  Roberto García-Vicente # 2,  Alba Rodríguez-García 2,  Armando Reyes-Palomares 3,  África Vincelle-Nieto 3,  Noemí Álvarez 2,  Alejandra Ortiz-Ruiz 2,  Vanesa Garrido-García 2,  Alicia Giménez 2,  Gonzalo Carreño-Tarragona 2,  Ricardo Sánchez 2,  Rosa Ayala 2 4,  Joaquín Martínez-López 2 4,  María Linares 5 6
Affiliations

Affiliations

  • 1 Department of Translational Hematology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Hospital 12 de Octubre - Centro Nacional de Investigaciones Oncológicas, CIBERONC, ES 28041, Madrid, Spain. [email protected].
  • 2 Department of Translational Hematology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Hospital 12 de Octubre - Centro Nacional de Investigaciones Oncológicas, CIBERONC, ES 28041, Madrid, Spain.
  • 3 Department of Biochemistry and Molecular Biology, Veterinary School, Universidad Complutense de Madrid, ES 28040, Madrid, Spain.
  • 4 Department of Medicine, Medicine School, Universidad Complutense de Madrid, ES 28040, Madrid, Spain.
  • 5 Department of Translational Hematology, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Hematological Malignancies Clinical Research Unit H12O-CNIO, Hospital 12 de Octubre - Centro Nacional de Investigaciones Oncológicas, CIBERONC, ES 28041, Madrid, Spain. [email protected].
  • 6 Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040, Madrid, Spain. [email protected].
  • # Contributed equally.
PMID: 37422594 DOI: 10.1038/s41375-023-01963-4
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 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.

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