RT Journal Article
SR Electronic
T1 Overcoming microenvironment-mediated chemoprotection through stromal galectin-3 inhibition in acute lymphoblastic leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.24.461149
DO 10.1101/2021.09.24.461149
A1 Somayeh S. Tarighat
A1 Fei Fei
A1 Eun Ji Joo
A1 Hisham Abdel-Azim
A1 Lu Yang
A1 Huimin Geng
A1 Khuchtumur Bum-Erdene
A1 I. Darren Grice
A1 Mark von Itzstein
A1 Helen Blanchard
A1 Nora Heisterkamp
YR 2021
UL http://biorxiv.org/content/early/2021/09/24/2021.09.24.461149.abstract
AB Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells including a dose-dependent reduction of viability and proliferation, induction of apoptosis and, importantly, inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.Competing Interest StatementThe authors have declared no competing interest.