TY - JOUR
T1 - Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts
AU - Fuka, G
AU - Kantner, H-P
AU - Grausenburger, R
AU - Inthal, A
AU - Bauer, E
AU - Krapf, G
AU - Kaindl, U
AU - Kauer, M
AU - Dworzak, M N
AU - Stoiber, D
AU - Haas, O A
AU - Panzer-Grümayer, R
PY - 2012/5
Y1 - 2012/5
N2 - 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.
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.
KW - Animals
KW - Cell Line, Tumor
KW - Core Binding Factor Alpha 2 Subunit/genetics
KW - Gene Silencing
KW - Humans
KW - Mice
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Proto-Oncogene Proteins c-ets/genetics
KW - RNA Interference
KW - Real-Time Polymerase Chain Reaction
KW - Repressor Proteins/genetics
KW - Signal Transduction
KW - TOR Serine-Threonine Kinases/metabolism
KW - Transplantation, Heterologous
KW - ETS Translocation Variant 6 Protein
UR - http://www.scopus.com/inward/record.url?scp=84860750862&partnerID=8YFLogxK
U2 - 10.1038/leu.2011.322
DO - 10.1038/leu.2011.322
M3 - Journal article
C2 - 22094587
SN - 0887-6924
VL - 26
SP - 927
EP - 933
JO - Leukemia
JF - Leukemia
IS - 5
ER -