title: Stromal cell-mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling.
abstract: It is well established that the stromal niche exerts a protective effect on chronic lymphocytic leukemia (CLL) cells, thereby also affecting their drug sensitivity. One hallmark of malignant cells is metabolic reprogramming, which is mostly represented by a glycolytic shift known as the Warburg effect. Because treatment resistance can be linked to metabolic alterations, we investigated whether bone marrow stromal cells impact the bioenergetics of primary CLL cells. In fact, stromal contact led to an increase of aerobic glycolysis and the cells' overall glycolytic capacity accompanied by an increased glucose uptake, expression of glucose transporter, and glycolytic enzymes. Activation of Notch signaling and of its direct transcriptional target c-Myc contributed to this metabolic switch. Based on these observations, CLL cells' acquired increased glucose dependency as well as Notch-c-Myc signaling could be therapeutically exploited in an effort to overcome stroma-mediated drug resistance.
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany;
authors.forename: Regina
authors.initials: R
authors.lastname: Jitschin
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany;
authors.forename: Martina
authors.initials: M
authors.lastname: Braun
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany;
authors.forename: Mirjeta
authors.initials: M
authors.lastname: Qorraj
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany;
authors.forename: Domenica
authors.initials: D
authors.lastname: Saul
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden;
authors.forename: Katarina
authors.initials: K
authors.lastname: Le Blanc
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; and Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany;
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mougiakakos
mesh_terms: D000332:Aerobiosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism; D019069:Cell Respiration / Q000235:genetics; D002478:Cells, Cultured; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch