title: DNA damage response and inflammatory signaling limit the MLL-ENL-induced leukemogenesis in vivo.
abstract: 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(CIP1) 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.
authors.affiliation: Department of Biology, Palacky University, Olomouc, Czech Republic.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Takacova
authors.forename: Robert
authors.initials: R
authors.lastname: Slany
authors.forename: Jirina
authors.initials: J
authors.lastname: Bartkova
authors.forename: Viktor
authors.initials: V
authors.lastname: Stranecky
authors.forename: Petr
authors.initials: P
authors.lastname: Dolezel
authors.forename: Pavla
authors.initials: P
authors.lastname: Luzna
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Vladimir
authors.initials: V
authors.lastname: Divoky
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C493508:Mllt1 protein, mouse; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D002110:Caffeine; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse