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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4102-4110.
Prepublished online as a Blood First Edition Paper on February 19, 2004; DOI 10.1182/blood-2003-07-2431.
Submitted July 18, 2003
Accepted February 3, 2004
Modification of Hematopoietic Stem Cell Fate By 5aza 2'deoxycytidine and Trichostatin A
Mohammed Milhem, Nadim Mahmud, Donald Lavelle, Hiroto Araki, Joseph Desimone, Yogen Saunthararajah, and Ronald Hoffman*
Hematology/ Oncology, University of Illinois Cancer Care Center, Chicago, IL, USA
* Corresponding author; email: ronhoff{at}uic.edu.
Efforts to change the fate of human hematopoietic stem cells (HSC) and progenitor cells (HPC) in-vitro have met with limited success. We hypothesized that previously utilized in-vitro conditions might result in silencing of genes required for the maintenance of primitive HSC/HPC. DNA methylation and histone deacetylation are components of an epigenetic program that regulates gene expression. Using pharmacological agents in-vitro that might possibly interfere with DNA methylation and histone deacetylation we attempted to maintain and expand cells with phenotypic and functional characteristics of primitive HSC/HPC. Human marrow CD34+ cells were exposed to a cytokine cocktail favoring differentiation in combination with 5aza 2deoxycytidine (5azaD) and trichostatin A (TSA) resulting in a significant expansion of a subset of CD34+ cells that possessed phenotypic properties as well as the proliferative potential characteristic of primitive HSC/HPC. In addition 5azaD and TSA pre-treated cells but not the CD34+ cells exposed to cytokines alone retained the ability to repopulate immunodeficient mice. Our findings demonstrate that 5azaD and TSA can be used to alter the fate of primitive HSC/HPC during in vitro culture.
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