PMID- 18317450
OWN - NLM
STAT- MEDLINE
DCOM- 20080807
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 27
IP  - 29
DP  - 2008 Jul 3
TI  - Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential 
      to hematopoietic cells.
PG  - 4096-106
LID - 10.1038/onc.2008.40 [doi]
AB  - 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.
FAU - Horn, S
AU  - Horn S
AD  - Department of Hematology and Oncology, University of Gottingen, Gottingen, 
      Germany.
FAU - Bergholz, U
AU  - Bergholz U
FAU - Jucker, M
AU  - Jucker M
FAU - McCubrey, J A
AU  - McCubrey JA
FAU - Trumper, L
AU  - Trumper L
FAU - Stocking, C
AU  - Stocking C
FAU - Basecke, J
AU  - Basecke J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080303
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acid Substitution
MH  - Animals
MH  - Cell Line
MH  - Cell Transformation, Neoplastic/genetics/*metabolism
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Disease Models, Animal
MH  - Enzyme Activation/genetics
MH  - Hematopoietic Stem Cells/*enzymology/pathology
MH  - Humans
MH  - Leukemia, Myeloid, Acute/*enzymology/genetics
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mutation, Missense
MH  - Neoplastic Stem Cells/*enzymology/pathology
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - *Point Mutation
MH  - Protein Kinases/genetics/metabolism
MH  - Protein Structure, Tertiary/genetics
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - Proto-Oncogene Proteins c-kit/genetics/metabolism
MH  - Signal Transduction/genetics
MH  - TOR Serine-Threonine Kinases
EDAT- 2008/03/05 09:00
MHDA- 2008/08/08 09:00
CRDT- 2008/03/05 09:00
PHST- 2008/03/05 09:00 [pubmed]
PHST- 2008/08/08 09:00 [medline]
PHST- 2008/03/05 09:00 [entrez]
AID - onc200840 [pii]
AID - 10.1038/onc.2008.40 [doi]
PST - ppublish
SO  - Oncogene. 2008 Jul 3;27(29):4096-106. doi: 10.1038/onc.2008.40. Epub 2008 Mar 3.