Browsing by Author "Graham, Douglas K."

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    Critical role of ASCT2-mediated amino acid metabolism in promoting leukaemia development and progression
    (Springer Nature, 2019-03) Ni, Fang; Yu, Wen-Mei; Li, Zhiguo; Graham, Douglas K.; Jin, Lingtao; Kang, Sumin; Rossi, Michael R.; Li, Shiyong; Broxmeyer, Hal E.; Qu, Cheng-Kui; Microbiology and Immunology, School of Medicine
    Amino acid (AA) metabolism is involved in diverse cellular functions, including cell survival and growth, however it remains unclear how it regulates normal hematopoiesis versus leukemogenesis. Here, we report that knockout of Slc1a5 (ASCT2), a transporter of neutral AAs, especially glutamine, results in mild to moderate defects in bone marrow and mature blood cell development under steady state conditions. In contrast, constitutive or induced deletion of Slc1a5 decreases leukemia initiation and maintenance driven by the oncogene MLL-AF9 or Pten deficiency. Survival of leukemic mice is prolonged following Slc1a5 deletion, and pharmacological inhibition of ASCT2 also decreases leukemia development and progression in xenograft models of human acute myeloid leukemia. Mechanistically, loss of ASCT2 generates a global effect on cellular metabolism, disrupts leucine influx and mTOR signaling, and induces apoptosis in leukemic cells. Given the substantial difference in reliance on ASCT2-mediated AA metabolism between normal and malignant blood cells, this in vivo study suggests ASCT2 as a promising therapeutic target for the treatment of leukemia.
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    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.