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

Author

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  • 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)

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.

Suggested Citation

  • 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, 2022. "Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28839-y
    DOI: 10.1038/s41467-022-28839-y
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    References listed on IDEAS

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    1. Reut Yosef & Noam Pilpel & Ronit Tokarsky-Amiel & Anat Biran & Yossi Ovadya & Snir Cohen & Ezra Vadai & Liat Dassa & Elisheva Shahar & Reba Condiotti & Ittai Ben-Porath & Valery Krizhanovsky, 2016. "Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL," Nature Communications, Nature, vol. 7(1), pages 1-11, September.
    2. Adela Hruby & Frank Hu, 2015. "The Epidemiology of Obesity: A Big Picture," PharmacoEconomics, Springer, vol. 33(7), pages 673-689, July.
    3. N. Giovannone & J. Liang & A. Antonopoulos & J. Geddes Sweeney & S. L. King & S. M. Pochebit & N. Bhattacharyya & G. S. Lee & A. Dell & H. R. Widlund & S. M. Haslam & C. J. Dimitroff, 2018. "Galectin-9 suppresses B cell receptor signaling and is regulated by I-branching of N-glycans," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
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