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

Author:

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

Abstract

AbstractThe 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.

Funder

U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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