View Item 
      •   Home
      • 1. Schools
      • College of Science
      • School of Biological Sciences (SBS)
      • SBS Theses (Open Access)
      • View Item
      •   Home
      • 1. Schools
      • College of Science
      • School of Biological Sciences (SBS)
      • SBS Theses (Open Access)
      • View Item
      JavaScript is disabled for your browser. Some features of this site may not work without it.
      Subject Lookup

      Browse

      All of DR-NTUCommunities & CollectionsTitlesAuthorsBy DateSubjectsThis CollectionTitlesAuthorsBy DateSubjects

      My Account

      Login

      Statistics

      Most Popular ItemsStatistics by CountryMost Popular Authors

      About DR-NTU

      Maintenance and expansion of hematopoietic stem cells in vitro using genetic methods.

      Thumbnail
      Tbs0603276c.pdf (17.00Mb)
      Author
      Wu, Zhihao.
      Date of Issue
      2011
      School
      School of Biological Sciences
      Abstract
      Chromosomal translocations encoding fusion proteins between N-terminal nucleoporin 98 (NUP98) and some members of the homeodomain protein superfamily have been observed recurrently in certain types of leukemia. Subsequent studies have shown that the ectopic expression of these leukemogenic or similar fusion genes in primitive bone marrow (BM) cells can induce hematopoietic stem cell (HSC) activity in these cells. We have extensively surveyed different branches of the homeodomain superfamily as partners to NUP98 in order to find fusion genes that could sustain HSC activity in BM cells in long-term continually expanding in vitro cultures. Remarkably, we found that CDX1, extended HOX subfamily member, when fused to NUP98, was able to sustain balanced HSC activity with high frequencies in massively expanding cultures as measured by robust long-term competitive in vivo transplantation assays. Interestingly, closely related NUP98-CDX4 induced leukemia with the shortest latency ever reported for NUP98-Homeodomain fusions unaided by MEIS1 transcription factor. Since HSC and leukemic stem cells (LSC) share similar self-renewal mechanisms, these pre-leukemic stem cells generated by the first genetic hits can provide useful models for elucidating the self-renewal mechanisms of HSC as well as LSC. We also found that NUP98-HOXA10 was able to reprogram B220+ cells in the bone marrow and conferred them long-term reconstituting multipotentiality in vivo. Transcriptional profiling of NUP98-HOXA10 transduced BM cells revealed that the aryl hydrocarbon receptor (AhR) pathway was the most suppressed pathway. Inhibition of this pathway using small molecule AhR inhibitor in combination with cytokine cocktail allowed 30-100 fold expansion of HSC in vitro. This provides an additional component to the elusive “magic” cocktail that allows maximal expansion of HSC ex vivo.
      Subject
      DRNTU::Science::Biological sciences
      Type
      Thesis
      Collections
      • SBS Theses (Open Access)

      Show full item record


      NTU Library, Nanyang Avenue, Singapore 639798 © 2011 Nanyang Technological University. All rights reserved.
      DSpace software copyright © 2002-2015  DuraSpace
      Contact Us | Send Feedback
      Share |    
      Theme by 
      Atmire NV
       

       


      NTU Library, Nanyang Avenue, Singapore 639798 © 2011 Nanyang Technological University. All rights reserved.
      DSpace software copyright © 2002-2015  DuraSpace
      Contact Us | Send Feedback
      Share |    
      Theme by 
      Atmire NV
       

       

      DCSIMG