Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Acute lymphoblastic leukemia (ALL) treatment relies on chemotherapy, but resistance and relapse remain significant challenges.
• Mechanisms underlying chemotherapy resistance in ALL are not fully understood.
• Nucleolin (NCL), a multifunctional nucleolar protein, is investigated for its role in ALL drug resistance.

Purpose of the Study:

• To identify factors associated with chemotherapy resistance in ALL.
• To investigate the link between nucleolin (NCL) expression and drug resistance in ALL.
• To evaluate NCL as a potential therapeutic target for overcoming ALL chemotherapy resistance.

Main Methods:

• Compared NCL mRNA and protein levels in ALL cell lines and patient samples using qRT-PCR and immunoblotting.
• Analyzed NCL mRNA levels in relation to disease stage using clinical specimens and public datasets.
• Assessed the impact of NCL inhibition on ALL chemotherapy effectiveness in cell lines and patient-derived xenograft mouse models.

Main Results:

• Found a strong correlation between high NCL abundance and disease relapse or poor survival in B-cell ALL (B-ALL).
• Demonstrated that altering NCL expression affects drug sensitivity in ALL cell lines.
• Showed that high NCL upregulates ATP-binding cassette transporters via ERK pathway activation, decreasing drug accumulation.
• Confirmed that targeting NCL with AS1411 enhances sensitivity to chemotherapeutic drugs and prolongs survival in ALL models.

Conclusions:

• Nucleolin (NCL) serves as a prognostic marker in B-ALL.
• NCL represents a potential therapeutic target to overcome chemotherapy resistance in ALL.
• Targeting NCL offers a promising strategy to improve treatment outcomes for ALL patients.