Browsing by Subject "Acute lymphocytic leukaemia"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Obesity-induced galectin-9 is a therapeutic target in B-cell acute lymphoblastic leukemia
    (Springer Nature, 2022-03-03) Lee, Miyoung; Hamilton, Jamie A.G.; Talekar, Ganesh R.; Ross, Anthony J.; Michael, Langston; Rupji, Manali; Dwivedi, Bhakti; Raikar, Sunil S.; Boss, Jeremy; Scharer, Christopher D.; Graham, Douglas K.; DeRyckere, Deborah; Porter, Christopher C.; Henry, Curtis J.; Pediatrics, School of Medicine
    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.
  • Thumbnail Image
    Item
    Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL
    (Springer Nature, 2019-11-26) Rodriguez, Sonia; Abundis, Christina; Boccalatte, Francesco; Mehrotra, Purvi; Chiang, Mark Y.; Yui, Mary A.; Wang, Lin; Zhang, Huajia; Zollman, Amy; Bonfim-Silva, Ricardo; Kloetgen, Andreas; Palmer, Joycelynne; Sandusky, George; Wunderlich, Mark; Kaplan, Mark H.; Mulloy, James C.; Marcucci, Guido; Aifantis, Iannis; Cardoso, Angelo A.; Carlesso, Nadia; Medicine, School of Medicine
    Timed degradation of the cyclin-dependent kinase inhibitor p27Kip1 by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27Kip1 pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).