Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia

Miyoung Lee,Christopher C Porter,Manali Rupji,Christopher D Scharer,Ganesh R Talekar,Curtis J Henry,Langston Michael,Douglas K Graham,Bhakti Dwivedi,Jeremy Boss,Anthony J Ross,Deborah Deryckere,Jamie A G Hamilton,Sunil S Raikar

doi:10.1038/s41467-022-28839-y

Abstract

The incidence of obesity is rising with greater than 40% of the world’s population expected to be overweight or suffering from obesity by 2030. This is alarming because obesity increases mortality rates in patients with various cancer subtypes including leukemia. The survival differences between lean patients and patients with obesity are largely attributed to altered drug pharmacokinetics in patients receiving chemotherapy; whereas, the direct impact of an adipocyte-enriched microenvironment on cancer cells is rarely considered. Here we show that the adipocyte secretome upregulates the surface expression of Galectin-9 (GAL-9) on human B-acute lymphoblastic leukemia cells (B-ALL) which promotes chemoresistance. Antibody-mediated targeting of GAL-9 on B-ALL cells induces DNA damage, alters cell cycle progression, and promotes apoptosis in vitro and significantly extends the survival of obese but not lean mice with aggressive B-ALL. Our studies reveal that adipocyte-mediated upregulation of GAL-9 on B-ALL cells can be targeted with antibody-based therapies to overcome obesity-induced chemoresistance.

Highlights

We show that adipocytes induce Galectin-9 (GAL-9) surface expression on human B-acute lymphoblastic leukemia cells (B-Acute Lymphoblastic Leukemia (ALL)) and that the induction of this lectin is protective against environmental and chemotherapyinduced cytotoxicity
Relative to responses observed in human B-acute lymphoblastic leukemia cells (B-ALL) cells cultured in unconditioned medium and stromal cellconditioned medium (SCM), we observed significant increases in β-Gal activity in every human B-ALL cell line cultured in adipocyte-conditioned medium (ACM) (Fig. 2d)
These observations highlight that adipocyteinduced “priming” of B-ALL cells can be exploited to induce extensive apoptosis when the GAL-9 mediated “brake” is inhibited (Fig. 7f, g). Inhibiting this mechanism in B-ALL cells in adipose-rich microenvironments represents an unexplored therapeutic approach as an alternative treatment strategy for a subset of patients with B-ALL. In these studies, we show that in the absence of chemotherapy treatment, adipocytes promote the aggregation of human B-ALL cells and induce cellular senescence, which coincides with the activation of senescence-promoting mediators (AKT, BCL-xL, ERK, and XIAP)

Summary

Introduction

The incidence of obesity is rising with greater than 40% of the world’s population expected to be overweight or suffering from obesity by 2030. Adipocytes supported the growth of LICs and protected them from the cytotoxic effects of chemotherapies by secreting lipids and amino acids that LICs can use for β-oxidation and glutaminolysis, respectively[14,15] This is not a passive process given the recent findings that leukemia cells in gonadal adipose tissue induce lipolysis in adipocytes, and the secreted lipids are subsequently transported into leukemia cells using the fatty acid transporter CD3616. These results highlight the impact of adipocytes on the function of HSCs and LICs. These results highlight the impact of adipocytes on the function of HSCs and LICs Despite these discoveries, we still lack effective treatment strategies to improve therapeutic outcomes in overweight and patients with obesity[17–20]. We demonstrate that αGAL-9 antibody treatment is highly cytotoxic to B-ALL cells in vitro and significantly extends the survival of obese mice with B-ALL

Methods

Results

Conclusion