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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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The RNA helicases DDX19A/B modulate selinexor sensitivity by regulating MCL1 mRNA nuclear export in leukemia cells

Tatsuya Terasaki1, Yuichiro Semba1,2, Kensuke Sasaki1,3

  • 1Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

Leukemia
|July 10, 2024
PubMed

Insights

Selinexor sensitivity in leukemia is regulated by DDX19A/B RNA helicases controlling MCL1 export. Targeting these helicases alongside selinexor induces apoptosis, suggesting DDX19A/B as potential biomarkers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Selinexor, an exportin1 (XPO1) inhibitor, shows anti-tumor potential but faces clinical limitations due to toxicity and lack of predictive biomarkers.
  • Identifying molecular regulators of selinexor sensitivity is crucial for optimizing its therapeutic application in leukemia.

Purpose of the Study:

  • To uncover key molecules and pathways influencing selinexor sensitivity in B-acute lymphoblastic leukemia (B-ALL).
  • To investigate the role of DDX19A and DDX19B RNA helicases in selinexor response and MCL1 regulation.

Main Methods:

  • Genome-wide CRISPR/Cas9 dropout screens were employed in B-ALL cell lines.
  • MCL1 mRNA nuclear export and protein levels were assessed following DDX19A/B depletion.
  • Synergistic effects of selinexor and DDX19A/B depletion on leukemia cell apoptosis were evaluated.
  • Depmap datasets were analyzed to assess DDX19B expression in T-ALL lines.

Main Results:

  • DDX19A and DDX19B were identified as novel modulators of selinexor sensitivity by regulating MCL1 mRNA nuclear export.
  • Dual depletion of DDX19A/B significantly reduced MCL1 protein levels and enhanced selinexor-induced apoptosis.
  • MCL1 overexpression rescued the apoptotic effect, confirming its role in selinexor sensitivity.
  • T-ALL lines with low DDX19B expression showed sensitivity to selinexor or DDX19A depletion.

Conclusions:

  • Exportin1 (XPO1) and DDX19A/B RNA helicases coordinately regulate cellular MCL1 levels.
  • DDX19A/B paralogs show promise as biomarkers for predicting selinexor treatment response.
  • Targeting DDX19 paralogs presents a potential therapeutic strategy to induce apoptosis in leukemia.

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