title: Silencing of ETV6/RUNX1 abrogates PI3K/AKT/mTOR signaling and impairs reconstitution of leukemia in xenografts.
abstract: 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.
authors.affiliation: Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Medical University Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Fuka
authors.forename: H-P
authors.initials: HP
authors.lastname: Kantner
authors.forename: R
authors.initials: R
authors.lastname: Grausenburger
authors.forename: A
authors.initials: A
authors.lastname: Inthal
authors.forename: E
authors.initials: E
authors.lastname: Bauer
authors.forename: G
authors.initials: G
authors.lastname: Krapf
authors.forename: U
authors.initials: U
authors.lastname: Kaindl
authors.forename: M
authors.initials: M
authors.lastname: Kauer
authors.forename: M N
authors.initials: MN
authors.lastname: Dworzak
authors.forename: D
authors.initials: D
authors.lastname: Stoiber
authors.forename: O A
authors.initials: OA
authors.lastname: Haas
authors.forename: R
authors.initials: R
authors.lastname: Panzer-Grümayer
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014183:Transplantation, Heterologous; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; D000097764:ETS Translocation Variant 6 Protein; C493728:RUNX1 protein, human; C546842:MTOR protein, human