Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic...

Area of Science:

• Hematology
• Cancer Biology
• Molecular Medicine

Background:

• Environmentally-mediated drug resistance is a major cause of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
• Bone marrow stromal cells protect leukemia cells via secreted chemokines, promoting migration and adhesion.
• Stromal galectin-3 mediates communication between stromal and BCP-ALL cells.

Purpose of the Study:

• To investigate the role of stromal galectin-3 in BCP-ALL cell behavior and drug resistance.
• To evaluate the therapeutic potential of galectin-3 inhibitors in BCP-ALL treatment.

Main Methods:

• CRISPR/Cas9 genome editing was used to ablate galectin-3 in stromal cells.
• BCP-ALL cells were co-cultured with control and galectin-3-knockout stromal cells.
• Novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) targeting galectin-3 were tested.

Main Results:

• Stromal galectin-3 is essential for BCP-ALL cell migration and adhesion to stromal cells.
• Loss of stromal galectin-3 sensitized BCP-ALL cells to conventional chemotherapy.
• Galectin-3 inhibitors (Cpd14 and Cpd17) replicated these effects, reducing viability, proliferation, and inducing apoptosis.
• These compounds also inhibited drug resistance in BCP-ALL cells.

Conclusions:

• Stromal galectin-3 plays a critical role in mediating BCP-ALL drug resistance through leukemia-stroma interactions.
• Targeting galectin-3 with small molecule inhibitors can overcome chemotherapy resistance in BCP-ALL.
• Combination therapy of galectin-3 inhibition with conventional drugs shows promise for treating BCP-ALL.