HOXB4 Is An Activator of HSC Self-Renewal

Summary

Principal Investigator: Guy Sauvageau
Abstract: The capacity for sustained self-renewal is one of the defining features of hematopoietic stem cells (HSCs). However, the molecular bases for HSC self-renewal remain obscure. We have previously reported that HSC expansion is profoundly affected by Hoxb4 overexpression and more recently developed HOXB4- based reagents and strategies which provide tools for deepening our knowledge of self-renewal mechanisms, and for achievement of clinically useful levels of HSC expansion. Four aims are proposed in this first renewal application: 1-To enhance the potential of HSCs to expand in vitro. This will be investigated first by varying Hoxb4 and Pbxl levels in HSCs as recently reported with our in vivo studies and by testing novel Hox-containing fusion genes with enhanced potential for HSC expansion. The contribution of growth factors and precursor differentiation stage (e.g., HSC vs MPP, etc) to HOXB4-driven HSC expansion will also be assessed. 2-To develop and test clinically-relevant strategies aimed at achieving a maximal expansion of HSCs in vitro. This includes the generation of soluble reagents that will interfere with the function of PBX1 and by testing the function of stabilized HOXB4 proteins. Studies with human HSCs will be conducted and effects of the manipulation evaluated by xenotransplantation using NOD/SCID mice and fetal sheep as recipients. 3-To identify a HOXB4-containing "HSC-self-renewal protein complex" and determine the role of the newly identified proteins in HSC self-renewal. Strategies include the utilization of a functional tandem affinity purification (TAP)-tagged HOXB4 and isolation of the complex in relevant cells. Identified proteins will be functionally validated using RNA interference. 4-To identify target genes to HOXB4 in purified mouse HSCs. This aim combines cell purification of newly characterized HSC populations with microarray analysis from small cell numbers and preliminary target gene validation.
Funding Period: 2000-07-01 - 2010-04-30
more information: NIH RePORT

Top Publications

  1. pmc Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions
    Hideaki Ohta
    Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
    Exp Hematol 35:817-30. 2007
  2. pmc Differential effects of HOXB4 on nonhuman primate short- and long-term repopulating cells
    Xiao Bing Zhang
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
    PLoS Med 3:e173. 2006
  3. pmc Prolonged self-renewal activity unmasks telomerase control of telomere homeostasis and function of mouse hematopoietic stem cells
    Sanja Sekulovic
    Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada
    Blood 118:1766-73. 2011
  4. pmc Ontogeny stage-independent and high-level clonal expansion in vitro of mouse hematopoietic stem cells stimulated by an engineered NUP98-HOX fusion transcription factor
    Sanja Sekulovic
    Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada
    Blood 118:4366-76. 2011
  5. pmc Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbx1(10) hematopoietic stem cells
    Sonia Cellot
    Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer IRIC, Montreal, QC, Canada
    Exp Hematol 35:802-16. 2007

Detail Information

Publications5

  1. pmc Near-maximal expansions of hematopoietic stem cells in culture using NUP98-HOX fusions
    Hideaki Ohta
    Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
    Exp Hematol 35:817-30. 2007
    ....
  2. pmc Differential effects of HOXB4 on nonhuman primate short- and long-term repopulating cells
    Xiao Bing Zhang
    Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
    PLoS Med 3:e173. 2006
    ..Here we examine, in a clinically relevant nonhuman primate model, the ability of HOXB4 to expand HSCs to potentially overcome this limitation...
  3. pmc Prolonged self-renewal activity unmasks telomerase control of telomere homeostasis and function of mouse hematopoietic stem cells
    Sanja Sekulovic
    Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada
    Blood 118:1766-73. 2011
    ..These findings document a role of telomerase in telomere homeostasis, and in preserving HSC functional integrity on prolonged self-renewal stimulation...
  4. pmc Ontogeny stage-independent and high-level clonal expansion in vitro of mouse hematopoietic stem cells stimulated by an engineered NUP98-HOX fusion transcription factor
    Sanja Sekulovic
    Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada
    Blood 118:4366-76. 2011
    ..These findings point to the effects of NUP98-HOXA10hd on HSCs in vitro being mediated by promoting self-renewal and set the stage for further dissection of this process...
  5. pmc Sustained in vitro trigger of self-renewal divisions in Hoxb4hiPbx1(10) hematopoietic stem cells
    Sonia Cellot
    Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer IRIC, Montreal, QC, Canada
    Exp Hematol 35:802-16. 2007
    ..We thus put forward this strategy as an efficient in vitro HSC expansion tool, enabling a further step into the avenue of self-renewal molecular effectors...