Dataset: DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL-induced Leukemogenesis in vivo
Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe...
Activation 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.
- Species:
- mouse
- Samples:
- 29
- Source:
- E-GEOD-35038
- PubMed:
- 22516260
- Updated:
- Dec.12, 2014
- Registered:
- Nov.24, 2014
Sample | DISEASE STAGE | ORGANISM PART | TIME OF TAMOXIFEN TREATMENT | CELLULAR STATE |
---|---|---|---|---|
GSM861215 | not specified | bone marrow | 7 months of tamoxifen treatment in vivo | high proliferation state with low DDR signaling |
GSM861215 | not specified | bone marrow | 7 months of tamoxifen treatment in vivo | high proliferation state with low DDR signaling |
GSM861215 | not specified | bone marrow | 7 months of tamoxifen treatment in vivo | high proliferation state with low DDR signaling |
GSM861215 | not specified | bone marrow | 7 months of tamoxifen treatment in vivo | high proliferation state with low DDR signaling |
GSM861219 | not specified | bone marrow | from 7 to 8 months of tamoxifen treatment in vivo | the transition period of lower proliferation and high DDR activity |
GSM861219 | not specified | bone marrow | from 7 to 8 months of tamoxifen treatment in vivo | the transition period of lower proliferation and high DDR activity |
GSM861219 | not specified | bone marrow | from 7 to 8 months of tamoxifen treatment in vivo | the transition period of lower proliferation and high DDR activity |
GSM861219 | not specified | bone marrow | from 7 to 8 months of tamoxifen treatment in vivo | the transition period of lower proliferation and high DDR activity |
GSM861223 | not specified | bone marrow | 8 months of tamoxifen treatment in vivo | senescence |
GSM861223 | not specified | bone marrow | 8 months of tamoxifen treatment in vivo | senescence |
GSM861223 | not specified | bone marrow | 8 months of tamoxifen treatment in vivo | senescence |
GSM861226 | not specified | bone marrow | 8 months of tamoxifen treatment in vivo | not specified |
GSM861227 | not specified | bone marrow | 7 months of tamoxifen treatment in vivo | not specified |
GSM861227 | not specified | bone marrow | 7 months of tamoxifen treatment in vivo | not specified |
GSM861227 | not specified | bone marrow | 7 months of tamoxifen treatment in vivo | not specified |
GSM861230 | early - induced proliferation and DDR | spleen | 7 months of tamoxifen treatment in vivo | not specified |
GSM861230 | early - induced proliferation and DDR | spleen | 7 months of tamoxifen treatment in vivo | not specified |
GSM861230 | early - induced proliferation and DDR | spleen | 7 months of tamoxifen treatment in vivo | not specified |
GSM861233 | progression - partial senescence and DDR is maintained | spleen | 10 months of tamoxifen treatment in vivo | not specified |
GSM861233 | progression - partial senescence and DDR is maintained | spleen | 10 months of tamoxifen treatment in vivo | not specified |
GSM861235 | progression - partial senescence and DDR is maintained | spleen | 9 months of tamoxifen treatment in vivo | not specified |
GSM861236 | terminal stage - proliferation, low or absent DDR and no senescence | spleen | 21 months of tamoxifen treatment in vivo | not specified |
GSM861237 | terminal stage - proliferation, low or absent DDR and no senescence | spleen | 23 months of tamoxifen treatment in vivo | not specified |
GSM861238 | terminal stage - proliferation, low or absent DDR and no senescence | spleen | 19 months of tamoxifen treatment in vivo | not specified |
GSM861239 | not specified | spleen | 24 months of tamoxifen treatment in vivo | not specified |
GSM861240 | not specified | spleen | 8 months of tamoxifen treatment in vivo | not specified |
GSM86124 | not specified | spleen | 9 months of tamoxifen treatment in vivo | not specified |
GSM861242 | not specified | spleen | 11 months of tamoxifen treatment in vivo | not specified |
GSM861242 | not specified | spleen | 11 months of tamoxifen treatment in vivo | not specified |