title: Downregulation of Prdm16 mRNA is a specific antileukemic mechanism during HOXB4-mediated HSC expansion in vivo.
abstract: Overexpression of HOXB4 in hematopoietic stem cells (HSCs) leads to increased self-renewal without causing hematopoietic malignancies in transplanted mice. The molecular basis of HOXB4-mediated benign HSC expansion in vivo is not well understood. To gain further insight into the molecular events underlying HOXB4-mediated HSC expansion, we analyzed gene expression changes at multiple time points in Lin(-)Sca1(+)c-kit(+) cells from mice transplanted with bone marrow cells transduced with a MSCV-HOXB4-ires-YFP vector. A distinct HOXB4 transcriptional program was reproducibly induced and stabilized by 12 weeks after transplant. Dynamic expression changes were observed in genes critical for HSC self-renewal as well as in genes involved in myeloid and B-cell differentiation. Prdm16, a transcription factor associated with human acute myeloid leukemia, was markedly repressed by HOXB4 but upregulated by HOXA9 and HOXA10, suggesting that Prdm16 downregulation was involved in preventing leukemia in HOXB4 transplanted mice. Functional evidence to support this mechanism was obtained by enforcing coexpression of sPrdm16 and HOXB4, which led to enhanced self-renewal, myeloid expansion, and leukemia. Altogether, these studies define the transcriptional pathways involved in HOXB4 HSC expansion in vivo and identify repression of Prdm16 transcription as a mechanism by which expanding HSCs avoid leukemic transformation.
authors.affiliation: Experimental Hematology Division, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN; Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN;
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, TN; and.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: Han M
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Experimental Hematology Division, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Experimental Hematology Division, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
authors.forename: Bernard G
authors.initials: BG
authors.lastname: Forget
authors.affiliation: Experimental Hematology Division, Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN;
authors.forename: Brian P
authors.initials: BP
authors.lastname: Sorrentino
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D014161:Transduction, Genetic
chemical_list: D004268:DNA-Binding Proteins; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; D009363:Neoplasm Proteins; C521133:Prdm16 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; C097899:homeobox protein HOXA9; C092119:Hoxa10 protein, mouse
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