title: Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells.
abstract: Constitutive activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway is observed in up to 70% of acute myelogenous leukemia. To investigate the relevance of an intrinsic PI3K-AKT pathway activation in hematopoietic malignancies, we analysed the effect of point mutations in the catalytic (p110alpha) and regulatory (p85alpha) subunit of class IA PI3K. We demonstrated that mutations in the helical (E542K, E545A) and kinase domain (H1047R) of p110alpha constitutively activate the PI3K-AKT pathway and lead to factor-independent growth of early hematopoietic cells. Proliferation and survival of the cells were inhibited in a time- and dose-dependent manner using either PI3K or AKT inhibitors. The mammalian target of rapamycin (mTOR) was demonstrated to be important for mitogenic, but not antiapoptotic signaling of mutant p110alpha. In a syngenic mouse model, hematopoietic cells expressing mutated p110alpha induced a leukemia-like disease characterized by anemia, neoplastic infiltration of hematopoietic organs and 90% mortality within 5 weeks, whereas activated mutants of the receptor tyrosine kinase c-KIT led to 100% mortality within 10 days. Our data show that point mutations in the p110alpha subunit of class IA PI3K confer factor independence to hematopoietic cells in vitro and leukemogenic potential in vivo, but have lower transforming activity than a deregulated class III receptor tyrosine kinase.
authors.affiliation: Department of Hematology and Oncology, University of Göttingen, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Horn
authors.forename: U
authors.initials: U
authors.lastname: Bergholz
authors.forename: M
authors.initials: M
authors.lastname: Jücker
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: L
authors.initials: L
authors.lastname: Trümper
authors.forename: C
authors.initials: C
authors.lastname: Stocking
authors.forename: J
authors.initials: J
authors.lastname: Bäsecke
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C484760:PIK3CA protein, human