title: The JAK2V617F oncogene requires expression of inducible phosphofructokinase/fructose-bisphosphatase 3 for cell growth and increased metabolic activity.
abstract: Myeloproliferative neoplasms are characterized by overproduction of myeloid lineage cells with frequent acquisition of oncogenic JAK2V617F kinase mutations. The molecular mechanisms that regulate energy requirements in these diseases are poorly understood. Transformed cells tend to rely on fermentation instead of more efficient oxidative phosphorylation for energy production. Our data in JAK2V617F-transformed cells show that growth and metabolic activity were strictly dependent on the presence of glucose. Uptake of glucose and cell surface expression of the glucose transporter Glut1 required the oncogenic tyrosine kinase. Importantly, JAK2V617F as well as active STAT5 increased the expression of the inducible rate-limiting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), which controls glycolytic flux through 6-phosphofructo-1-kinase. PFKFB3 was required for JAK2V617F-dependent lactate production, oxidative metabolic activity and glucose uptake. Targeted knockdown of PFKFB3 also limited cell growth under normoxic and hypoxic conditions and blocked in vivo tumor formation in mice. Overall, these data suggest that inducible PFKFB3 is required for increased growth, metabolic activity and is regulated through active JAK2 and STAT5. Novel therapies that specifically block PFKFB3 activity or expression would, therefore, be expected to inhibit JAK2/STAT5-dependent malignancies and related cancers.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Reddy
authors.forename: M S
authors.initials: MS
authors.lastname: Fernandes
authors.forename: A
authors.initials: A
authors.lastname: Deshpande
authors.forename: E
authors.initials: E
authors.lastname: Weisberg
authors.forename: H V
authors.initials: HV
authors.lastname: Inguilizian
authors.forename: O
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: A L
authors.initials: AL
authors.lastname: Kung
authors.forename: R L
authors.initials: RL
authors.lastname: Levine
authors.forename: J D
authors.initials: JD
authors.lastname: Griffin
authors.forename: M
authors.initials: M
authors.lastname: Sattler
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D006597:Fructose-Bisphosphatase / Q000235:genetics* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D025481:Phosphofructokinase-2 / Q000235:genetics* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051272:Glucose Transporter Type 1; D050799:STAT5 Transcription Factor; D025481:Phosphofructokinase-2; D053614:Janus Kinase 2; D006597:Fructose-Bisphosphatase; D005947:Glucose