ArrayExpress Uploaderarrayexpress_sidmousenot specified7 months of tamoxifen treatment in vivobone marrowhigh proliferation state with low DDR signalingnot specified7 months of tamoxifen treatment in vivobone marrowhigh proliferation state with low DDR signalingnot specified7 months of tamoxifen treatment in vivobone marrowhigh proliferation state with low DDR signalingnot specified7 months of tamoxifen treatment in vivobone marrowhigh proliferation state with low DDR signalingnot specifiedfrom 7 to 8 months of tamoxifen treatment in vivobone marrowthe transition period of lower proliferation and high DDR activitynot specifiedfrom 7 to 8 months of tamoxifen treatment in vivobone marrowthe transition period of lower proliferation and high DDR activitynot specifiedfrom 7 to 8 months of tamoxifen treatment in vivobone marrowthe transition period of lower proliferation and high DDR activitynot specifiedfrom 7 to 8 months of tamoxifen treatment in vivobone marrowthe transition period of lower proliferation and high DDR activitynot specified8 months of tamoxifen treatment in vivobone marrowsenescencenot specified8 months of tamoxifen treatment in vivobone marrowsenescencenot specified8 months of tamoxifen treatment in vivobone marrowsenescencenot specified8 months of tamoxifen treatment in vivobone marrownot specifiednot specified7 months of tamoxifen treatment in vivobone marrownot specifiednot specified7 months of tamoxifen treatment in vivobone marrownot specifiednot specified7 months of tamoxifen treatment in vivobone marrownot specifiedearly - induced proliferation and DDR7 months of tamoxifen treatment in vivospleennot specifiedearly - induced proliferation and DDR7 months of tamoxifen treatment in vivospleennot specifiedearly - induced proliferation and DDR7 months of tamoxifen treatment in vivospleennot specifiedprogression - partial senescence and DDR is maintained10 months of tamoxifen treatment in vivospleennot specifiedprogression - partial senescence and DDR is maintained10 months of tamoxifen treatment in vivospleennot specifiedprogression - partial senescence and DDR is maintained9 months of tamoxifen treatment in vivospleennot specifiedterminal stage - proliferation, low or absent DDR and no senescence21 months of tamoxifen treatment in vivospleennot specifiedterminal stage - proliferation, low or absent DDR and no senescence23 months of tamoxifen treatment in vivospleennot specifiedterminal stage - proliferation, low or absent DDR and no senescence19 months of tamoxifen treatment in vivospleennot specifiednot specified24 months of tamoxifen treatment in vivospleennot specifiednot specified8 months of tamoxifen treatment in vivospleennot specifiednot specified9 months of tamoxifen treatment in vivospleennot specifiednot specified11 months of tamoxifen treatment in vivospleennot specifiednot specified11 months of tamoxifen treatment in vivospleennot specified860108Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe...22516260E-GEOD-35038/profile/8773/arrayexpressuploader429acute leukemiabonebone marrowcancercelldiseaseestrogenleukemiamyeloproliferative diseaseproteinspleenstem cellDec.12, 2014Falsedna-damage-response-and-inflammatory-signaling-limE-GEOD-35038_A-AFFY-36DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL-induced Leukemogenesis in vivoNov.24, 2014Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21 checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anti-cancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling towards senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development. We created a mouse model wherein the protein function of the MLL-ENL oncogene depends on tamoxifen due to fusion with the mutated estrogen-binding domain of the estrogen receptor (ERtm). After 7 months of tamoxifen administration, the MLL-ENL-ERtm mice developed a myeloproliferative disease, which progressed into the terminal stage after a long period (mean survival: 592 ± 112 days) of continuous tamoxifen provision. We have profiled gene expression at three time-points of tamoxifen treatment corresponding to three distinct cellular states of the MLL-ENL-ERtm-induced myeloproliferation in the bone marrow: 1. 7 months - high proliferation state with low DDR signaling (4 biological replicates), 2. 7-8 months - the transition period of lower proliferation and high DDR activity (4 biogical replicates) and 3. 8 months - the senescence (3 biological replicates). Time-matched tamoxifen-treated wild-type bone marrow analysed in 4 biological replicates. We have profiled gene expression in three disease stages in the spleen: 1. 7 months - early stage - induced proliferation and DDR (3 biological replicates), 2. 9-10 months - progression - partial senescence and DDR is maintained (3 biological replicates) and 3. 16-23 months - terminal stage - proliferation, low or absent DDR and no senescence (3 biological replicates). Time-matched tamoxifen-treated and age-matched wild-type spleens analysed in 5 biological replicates.http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-35038http://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-35038/samples/