DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL-Induced Leukemogenesis In Vivo

SummaryActivation 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/p21CIP1 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 anticancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling toward 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.

► MLL-ENL-ERtm triggers myeloproliferation progressing to acute leukemia in mice
► DDR and inflammation induce a pro-senescence program in a tissue-dependent manner
► DDR/Senescence delay/prevent full MLL-ENL-oncogene-induced leukemic transformation
► DDR inhibition accelerates transition to a self-renewing leukemia stem cell state