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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2315-2322.
Prepublished online as a Blood First Edition Paper on July 1, 2004; DOI 10.1182/blood-2004-01-0204.
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Submitted January 20, 2004
Accepted June 9, 2004
Constitutively Active Notch4 Promotes Early Human Hematopoietic Progenitor Cell Maintenance While Inhibiting Differentiation and Causes Lymphoid Abnormalities In Vivo
Suzanne M Vercauteren and Heather J Sutherland*
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver Hospital and Health Sciences Centre, Vancouver, B.C., Canada; Department of Medicine, University of British Columbia, Vancouver, B.C., Canada
* Corresponding author; email: hsutherl{at}bccancer.bc.ca.
Notch transmembrane receptors are known to play a critical role in cell fate decisions with Notch1 shown to enhance self renewal of hematopoietic stem cells and cause T cell leukemia. Four Notch receptors exist, and the extent of redundancy and overlap in their function is unknown. Notch4 is structurally distinct from Notch1-3 and has not been extensively studied in hematopoiesis. By PCR we find Notch4 transcript expression in human marrow cells and in both CD34+ and CD34- populations. When constitutively active Notch1 or 4 was overexpressed in normal human marrow or cord cells, we found reduced colony forming and short-term proliferative ability while the primitive progenitor content of myeloid long-term cultures was significantly increased. Notch4-IC transduced cord cells transplanted into  2-microglobulin NOD/SCID mice resulted in significantly higher levels of engraftment of both GFP+ and GFP- populations as compared to controls. GFP+ cells in bone marrow and spleen of transplanted animals gave rise to an immature CD4+/CD8+ T cell population, while B cell development was blocked. These results indicate that activation of Notch4 results in enhanced stem cell activity, reduced differentiation and altered lymphoid development suggesting it may influence both stem cells and the fate of the common lymphoid progenitor.
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