Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia.
Miyoung LeeJamie A G HamiltonGanesh R TalekarAnthony J RossLangston MichaelManali RupjiBhakti DwivediSunil S RaikarJeremy M BossChristopher D ScharerDouglas K GrahamDeborah DeRyckereChristopher C PorterCurtis J HenryPublished in: Nature communications (2022)
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.
Keyphrases
- insulin resistance
- weight loss
- high fat diet induced
- metabolic syndrome
- acute lymphoblastic leukemia
- cell cycle arrest
- adipose tissue
- induced apoptosis
- type diabetes
- weight gain
- cell cycle
- dna damage
- bariatric surgery
- endoplasmic reticulum stress
- oxidative stress
- end stage renal disease
- cell proliferation
- chronic kidney disease
- poor prognosis
- cell death
- endothelial cells
- high glucose
- ejection fraction
- body mass index
- diabetic rats
- bone marrow
- newly diagnosed
- single cell
- physical activity
- allogeneic hematopoietic stem cell transplantation
- coronary artery disease
- drug induced
- fatty acid
- postmenopausal women
- radiation therapy
- dna methylation
- bone mineral density
- gene expression
- young adults
- cardiovascular events
- rectal cancer
- long non coding rna