Adipocyte-secreted interleukin-9 promotes B-cell acute lymphoblastic leukemia 2636

Abstract Description Children diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) who present with obesity have increased mortality rates. Interleukin-9 (IL-9) is a cytokine which promotes the progression of blood cancers including acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL). Although IL-9 is mainly produced by CD4+ T-cell populations (mainly Th9 cells), our lab has made the novel discovery that IL-9 is produced by murine and human adipocytes. To determine how this cytokine impacts B-ALL progression, we found that recombinant IL-9 treatment activated STAT-1, STAT-3, and STAT-5 signaling pathways in malignant human B-cells. These responses correlated with increased protein levels of the proliferation regulators E2F1 and activation of retinoblastoma, which enhanced the growth of B-ALL cells. Furthermore, IL-9 stimulation significantly alters mitochondrial activity. These perturbations were highlighted by reductions in the protein level of the pro-apoptotic protein Bim and upregulation of mitochondrial ROS in several human B-ALL cell lines. Despite inducing the proliferation of B-ALL cells, IL-9 stimulated leukemia cells were more resistant to the cytotoxic effects of the chemotherapies methotrexate and doxorubicin. For the first time, these studies demonstrate that adipocytes produce IL-9, that IL-9 promotes the proliferation of human B-ALL cells, and that IL-9 mediated mitochondrial perturbations are associated with augmented chemoresistance. Funding Sources Supported by awards granted through Emory University/Aflac Cancer and Blood Disorders Center and The Patten Davis Foundation Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)