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

Miyoung Lee, Jamie A. G. Hamilton, Ganesh R. Talekar, Anthony J. Ross, Langston Michael, Manali Rupji, Bhakti Dwivedi, Sunil S. Raikar, Jeremy Boss, Christopher D. Scharer, Douglas K. Graham, Deborah DeRyckere, Christopher C. Porter and Curtis J. Henry ()
Additional contact information
Miyoung Lee: Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta
Jamie A. G. Hamilton: Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta
Ganesh R. Talekar: Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta
Anthony J. Ross: Indiana University School of Medicine, Indianapolis
Langston Michael: Wake Forest University
Manali Rupji: Winship Cancer Institute
Bhakti Dwivedi: Winship Cancer Institute
Sunil S. Raikar: Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta
Jeremy Boss: Emory University School of Medicine
Christopher D. Scharer: Emory University School of Medicine
Douglas K. Graham: Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta
Deborah DeRyckere: Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta
Christopher C. Porter: Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta
Curtis J. Henry: Emory University School of Medicine and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28839-y

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