PMID- 22094587
OWN - NLM
STAT- MEDLINE
DCOM- 20120705
LR  - 20231213
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Linking)
VI  - 26
IP  - 5
DP  - 2012 May
TI  - Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs 
      reconstitution of leukemia in xenografts.
PG  - 927-33
LID - 10.1038/leu.2011.322 [doi]
AB  - The ETV6/RUNX1 (E/R) gene fusion is generated by the t(12;21) and found in 
      approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia. In 
      contrast to the overwhelming evidence that E/R is critical for the initiation of 
      leukemia, its relevance for the maintenance of overt disease is less clear. To 
      investigate this issue, we suppressed the endogenous E/R fusion protein with 
      lentivirally transduced short hairpin RNA in the leukemia cell lines REH and 
      AT-2, and found a distinct reduction of proliferation and cell survival. In line 
      with the observed concurrent inactivation of the phosphoinositide 3-kinase 
      (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, pharmacological 
      inhibition diminished the phosphorylation of AKT and ribosomal protein S6, and 
      significantly increased the apoptosis rate in E/R-positive leukemias. Moreover, 
      PI3K/mTOR inhibitors sensitized glucocorticoid-resistant REH cells to 
      prednisolone, an observation of potential relevance for improving treatment of 
      drug-resistant relapses. Of note, knockdown of the E/R fusion gene also severely 
      impaired the repopulation capacity of REH cells in non-obese deficient/severe 
      combined immunodeficient mice. Collectively, these data demonstrate that the E/R 
      fusion protein activates the PI3K/AKT/mTOR pathway and is indispensible for 
      disease maintenance. Importantly, these results provide a first rationale and 
      justification for targeting the fusion gene and the PI3K/AKT/mTOR pathway 
      therapeutically.
FAU - Fuka, G
AU  - Fuka G
AD  - Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Medical 
      University Vienna, Vienna, Austria.
FAU - Kantner, H-P
AU  - Kantner HP
FAU - Grausenburger, R
AU  - Grausenburger R
FAU - Inthal, A
AU  - Inthal A
FAU - Bauer, E
AU  - Bauer E
FAU - Krapf, G
AU  - Krapf G
FAU - Kaindl, U
AU  - Kaindl U
FAU - Kauer, M
AU  - Kauer M
FAU - Dworzak, M N
AU  - Dworzak MN
FAU - Stoiber, D
AU  - Stoiber D
FAU - Haas, O A
AU  - Haas OA
FAU - Panzer-Grumayer, R
AU  - Panzer-Grumayer R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111118
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 (Core Binding Factor Alpha 2 Subunit)
RN  - 0 (Proto-Oncogene Proteins c-ets)
RN  - 0 (RUNX1 protein, human)
RN  - 0 (Repressor Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Core Binding Factor Alpha 2 Subunit/*genetics
MH  - *Gene Silencing
MH  - Humans
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*metabolism/pathology
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Proto-Oncogene Proteins c-ets/*genetics
MH  - RNA Interference
MH  - Real-Time Polymerase Chain Reaction
MH  - Repressor Proteins/*genetics
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transplantation, Heterologous
MH  - ETS Translocation Variant 6 Protein
EDAT- 2011/11/19 06:00
MHDA- 2012/07/06 06:00
CRDT- 2011/11/19 06:00
PHST- 2011/11/19 06:00 [entrez]
PHST- 2011/11/19 06:00 [pubmed]
PHST- 2012/07/06 06:00 [medline]
AID - leu2011322 [pii]
AID - 10.1038/leu.2011.322 [doi]
PST - ppublish
SO  - Leukemia. 2012 May;26(5):927-33. doi: 10.1038/leu.2011.322. Epub 2011 Nov 18.