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

Somayeh S Tarighat,Nora Heisterkamp,Hisham Abdel-Azim,Eun Ji Joo,Khuchtumur Bum-Erdene,Lu Yang,Fei Fei,Mark Von Itzstein,I Darren Grice,Huimin Geng,Helen Blanchard

doi:10.3390/ijms222212167

Abstract

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, the 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, the induction of apoptosis and, importantly, the 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.

Highlights

Relapse is a main cause of treatment failure for patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [1]
There is a marked increase in galectin-3 mRNA in the same samples, suggesting that chemotherapeutic treatment of the BM, including leukemia cells and cells in the leukemia microenvironment, induces high amounts of galectin-3
Higher levels of galectin-3 (LGALS3) mRNA correlate with a higher probability of being minimal residual disease (MRD)-positive at the end of such induction therapy (Figure S1B)

Summary

Introduction

Relapse is a main cause of treatment failure for patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [1]. The tumor microenvironment is a major contributing factor to relapse because it regulates the migration, survival, proliferation and response to drug treatment in BCP-ALL cells [2,3]. We and others have modeled the interaction between BCP-ALL cells and stroma in an ex vivo tissue co-culture model with OP9 bone marrow stromal cells to identify interactions that promote leukemia cell survival. Mesenchymal bone marrow stromal cells synthesize and secrete high amounts of galectin-3 (Gal3), a carbohydrate-binding protein with immunomodulatory activity (for example, [8,9,10]). Gal has a range of glycoconjugate ligands on the surface of cells, but intracellularly it binds proteins [13] and regulates a variety of functions, including growth and mRNA splicing [14,15,16]

Methods

Results

Conclusion