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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
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Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia

María Luz Morales1, Roberto García-Vicente2, Alba Rodríguez-García2

  • 1Department 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. marimo13@ucm.es.

Leukemia
|July 8, 2023
PubMed

Insights

Cytarabine resistance in acute myeloid leukemia (AML) involves altered RNA splicing and serine-arginine-rich (SR) protein phosphorylation. Splicing inhibitors show promise for treating AML, with a combination therapy demonstrating significant efficacy.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genomics

Background:

  • Cytarabine is a standard treatment for acute myeloid leukemia (AML), but high rates of drug resistance (85%) and low cure rates (10%) limit its effectiveness.
  • Understanding the molecular mechanisms underlying cytarabine resistance is crucial for developing improved therapeutic strategies.

Purpose of the Study:

  • To investigate the role of RNA splicing and serine-arginine-rich (SR) protein phosphorylation in cytarabine resistance in AML.
  • To evaluate the therapeutic potential of targeting RNA splicing in AML, including in combination with existing drugs.

Main Methods:

  • RNA sequencing (RNA-seq) and phosphoproteomics were employed to analyze molecular changes in cytarabine-resistant AML cells.
  • SR protein phosphorylation levels at diagnosis were compared between responder and non-responder patients.
  • The efficacy of splicing inhibitors, alone and in combination with other drugs (e.g., venetoclax), was assessed in AML cell lines and patient samples.

Main Results:

  • Cytarabine resistance was associated with significant alterations in RNA splicing patterns and SR protein phosphorylation.
  • Lower SR protein phosphorylation at diagnosis was observed in patients who responded to cytarabine, suggesting predictive value.
  • Splicing inhibitors demonstrated therapeutic efficacy against both sensitive and resistant AML cells, with a combination of H3B-8800 and venetoclax showing synergistic effects and no toxicity in healthy cells.

Conclusions:

  • RNA splicing inhibition represents a promising therapeutic strategy for AML, applicable to both newly diagnosed and relapsed/refractory cases.
  • Targeting RNA splicing, particularly in combination with venetoclax, offers a potential new treatment approach with demonstrated efficacy and safety.

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