Multiple mixed lineage leukemia (MLL) fusion proteins suppress p53-mediated response to DNA damage.
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are often observed in acute leukemias of both myeloid and lymphocytic origin. Expression of MLL fusion proteins is known to induce malignant transformation of normal blood progenitors; however, molecular mechanisms of this process are still poorly understood. In this study we investigated the effect of several frequently detected MLL fusion proteins on p53 transcriptional activity. Our data show that MLL-AF9, MLL-AF10, MLL-ENL, and MLL-ELL substantially down-regulate p53-mediated induction of p21, MDM2, and Bax in response to DNA damage. Furthermore, we identify the reduction in p53 acetylation by p300 as a major mechanism of the inhibitory effect of MLL leukemic fusions. Our data suggest that abrogation of p53 functional activity can be a common feature of MLL fusion-mediated leukemogenesis.
Wiederschain
Dmitri
D
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Kawai
Hidehiko
H
Shilatifard
Ali
A
Yuan
Zhi-Min
ZM
D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage; D017931:DNA Primers / Q000737:chemistry; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D051788:Myeloid-Lymphoid Leukemia Protein; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D011839:Radiation, Ionizing; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017931:DNA Primers; C470550:MLL-AF10 fusion protein, human; C474558:MLL-AF9 fusion protein, human; C472772:MLL-ELL fusion protein, human; C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D051788:Myeloid-Lymphoid Leukemia Protein; D012313:RNA; D008156:Luciferases