title: Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia.
abstract: Cooperation of multiple mutations is thought to be required for cancer development. In previous studies, murine myeloid leukemias induced by transducing wild-type bone marrow progenitors with a SRY sex determining region Y-box 4 (Sox4)-expressing retrovirus frequently carried proviral insertions at Sfpi1, decreasing its mRNA levels, suggesting that reduced Sfpi1 expression cooperates with Sox4 in myeloid leukemia induction. In support of this hypothesis, we show here that mice receiving Sox4 virus-infected Sfpi1(ko/+) bone marrow progenitors developed myeloid leukemia with increased penetrance and shortened latency. Interestingly, Sox4 expression further decreased Sfpi1 transcription. Ectopic SOX4 expression reduced endogenous PU.1 mRNA levels in HL60 promyelocytes, and decreased Sfpi1 mRNA levels were also observed in the spleens of leukemic and preleukemic mice receiving Sox4 virus-infected wild-type bone marrow cells. In addition, Sox4 protein bound to a critical upstream regulatory element of Sfpi1 in ChIP assays. Such cooperation probably occurs in de novo human acute myeloid leukemias, as an analysis of 285 acute myeloid leukemia patient samples found a significant negative correlation between SOX4 and PU.1 expression. Our results establish a novel cooperation between Sox4 and reduced Sfpi1 expression in myeloid leukemia development and suggest that SOX4 could be an important new therapeutic target in human acute myeloid leukemia.
authors: National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Georg
authors: G
authors: Aue
authors: Yang
authors: Y
authors: Du
authors: Susan M
authors: SM
authors: Cleveland
authors: Stephen B
authors: SB
authors: Smith
authors: Utpal P
authors: UP
authors: Davé
authors: Delong
authors: D
authors: Liu
authors: Marc A
authors: MA
authors: Weniger
authors: Jean Yves
authors: JY
authors: Metais
authors: Nancy A
authors: NA
authors: Jenkins
authors: Neal G
authors: NG
authors: Copeland
authors: Cynthia E
authors: CE
authors: Dunbar
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004843:Epistasis, Genetic / Q000502:physiology; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D057895:Haploinsufficiency / Q000502:physiology*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046228:Microarray Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D055751:SOXC Transcription Factors; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C489990:Sox4 protein, mouse