title: Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10.
abstract: Acquisition of self-renewal capability by myeloid progenitors to become leukemic stem cells during myeloid leukemia development is poorly understood. Here, we show that Setbp1 overexpression efficiently confers self-renewal capability to myeloid progenitors in vitro, causing their immortalization in the presence of stem cell factor and IL-3. Self-renewal after immortalization requires continuous Setbp1 expression. We also found that Hoxa9 and Hoxa10 mRNA are present at dramatically higher levels in Setbp1-immortalized cells compared with other immortalized cells, and are induced shortly after Setbp1 expression in primary myeloid progenitors. Suppression of either gene in Setbp1-immortalized cells drastically reduces their colony-forming capability. Interestingly, Setbp1 protein associates with Hoxa9 and Hoxa10 promoters in chromatin immunoprecipitation assays in these cells, suggesting that both are direct transcriptional targets of Setbp1. Setbp1 also promotes self-renewal of myeloid progenitors in vivo as its coexpression with BCR/ABL transforms primary mouse myeloid progenitors, generating aggressive leukemias in recipient mice resembling chronic myelogenous leukemia (CML) myeloid blast crisis. Increased SETBP1 mRNA levels were also detected in a subset of CML advanced phase/blast crisis patients with high levels of HOXA9 and HOXA10 expression. Thus, Setbp1 activation represents a novel mechanism conferring self-renewal capability to myeloid progenitors in myeloid leukemia development.
authors.affiliation: Department of Pediatrics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Oakley
authors.forename: Yufen
authors.initials: Y
authors.lastname: Han
authors.forename: Bandana A
authors.initials: BA
authors.lastname: Vishwakarma
authors.forename: Su
authors.initials: S
authors.lastname: Chu
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.forename: Kristbjorn O
authors.initials: KO
authors.lastname: Gudmundsson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Keller
authors.forename: Xiongfong
authors.initials: X
authors.lastname: Chen
authors.forename: Vasyl
authors.initials: V
authors.lastname: Vasko
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000502:physiology*; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C425066:SETBP1 protein, human; C574812:Setbp1 protein, mouse; C097899:homeobox protein HOXA9; C092119:Hoxa10 protein, mouse