title: Essential role of PU.1 in maintenance of mixed lineage leukemia-associated leukemic stem cells.
abstract: Acute myeloid leukemia is a clonal malignant disorder derived from a small number of leukemic stem cells (LSCs). Rearrangements of the mixed lineage leukemia (MLL) gene are found in acute myeloid leukemia associated with poor prognosis. The upregulation of Hox genes is critical for LSC induction and maintenance, but is unlikely to support malignancy and the high LSC frequency observed in MLL leukemias. The present study shows that MLL fusion proteins interact with the transcription factor PU.1 to activate the transcription of CSF-1R, which is critical for LSC activity. Acute myeloid leukemia is cured by either deletion of PU.1 or ablation of cells expressing CSF-1R. Kinase inhibitors specific for CSF-1R prolong survival time. These findings indicate that PU.1-mediated upregulation of CSF-1R is a critical effector of MLL leukemogenesis.
authors.affiliation: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Aikawa
authors.forename: Kazutsune
authors.initials: K
authors.lastname: Yamagata
authors.forename: Takuo
authors.initials: T
authors.lastname: Katsumoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shima
authors.forename: Mika
authors.initials: M
authors.lastname: Shino
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
authors.forename: Michael L
authors.initials: ML
authors.lastname: Cleary
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Issay
authors.initials: I
authors.lastname: Kitabayashi
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D005801:Genes, Homeobox; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D014411:Neoplastic Stem Cells; D010671:Phenylurea Compounds / Q000494:pharmacology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011495:Histone-Lysine N-Methyltransferase; D051788:Myeloid-Lymphoid Leukemia Protein; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D016186:Receptor, Macrophage Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D016559:Tacrolimus; D013844:Thiazoles; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C463061:AP20187; C517050:N-(4-((6,7-dimethoxy-4-quinolyl)oxy)-2-methoxyphenyl)-N'-(1-(1,3-thiazole-2-yl)ethyl)urea; C497423:Kmt2a protein, mouse
keywords: Acute myeloid leukemia; CSF-1R; Spi-1; mixed lineage leukemia; stem cells