title: Sox4 cooperates with CREB in myeloid transformation.
abstract: The cAMP response element-binding protein (CREB) is a nuclear transcription factor that is critical for normal and neoplastic hematopoiesis. Previous studies have demonstrated that CREB is a proto-oncogene whose overexpression promotes cellular proliferation in hematopoietic cells. Transgenic mice that overexpress CREB in myeloid cells develop a myeloproliferative disease with splenomegaly and aberrant myelopoiesis. However, CREB overexpressing mice do not spontaneously develop acute myeloid leukemia. In this study, we used retroviral insertional mutagenesis to identify genes that accelerate leukemia in CREB transgenic mice. Our mutagenesis screen identified several integration sites, including oncogenes Gfi1, Myb, and Ras. The Sox4 transcription factor was identified by our screen as a gene that cooperates with CREB in myeloid leukemogenesis. We show that the transduction of CREB transgenic mouse bone marrow cells with a Sox4 retrovirus increases survival and self-renewal of cells in vitro. Furthermore, leukemic blasts from the majority of acute myeloid leukemia patients have higher CREB, phosphorylated CREB, and Sox 4 protein expression. Sox4 transduction of mouse bone marrow cells results in increased expression of CREB target genes. We also demonstrate that CREB is a direct target of Sox4 by chromatin immunoprecipitation assays. These results indicate that Sox4 and CREB cooperate and contribute to increased proliferation of hematopoietic progenitor cells.
authors.affiliation: Department of Pediatrics and Pathology & Laboratory Medicine, Gwynne Hazen, Cherry Memorial Laboratories, Mattel Children's Hospital, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
authors.forename: Salemiz
authors.initials: S
authors.lastname: Sandoval
authors.forename: Christina
authors.initials: C
authors.lastname: Kraus
authors.forename: Er-Chieh
authors.initials: EC
authors.lastname: Cho
authors.forename: Michelle
authors.initials: M
authors.lastname: Cho
authors.forename: Juraj
authors.initials: J
authors.lastname: Bies
authors.forename: Elena
authors.initials: E
authors.lastname: Manara
authors.forename: Benedetta
authors.initials: B
authors.lastname: Accordi
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Landaw
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.forename: Martina
authors.initials: M
authors.lastname: Pigazzi
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Sakamoto
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011247:Pregnancy; D000090063:Proto-Oncogene Mas; D012190:Retroviridae / Q000235:genetics; D055751:SOXC Transcription Factors / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse