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Blood, 15 August 2004, Vol. 104, No. 4, pp. 986-992.
Prepublished online as a Blood First Edition Paper on April 22, 2004; DOI 10.1182/blood-2003-07-2277.
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Submitted July 8, 2003
Accepted April 1, 2004
Enforced expression of cyclin D2 enhances the proliferative potential of myeloid progenitors, accelerates in vivo myeloid reconstitution, and promotes rescue of mice from lethal myeloablation
Yutaka Sasaki, Christina T Jensen, Stefan Karlsson, and Sten E Jacobsen*
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden
Department of Molecular Medicine and Gene Therapy, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden
* Corresponding author; email: Sten.Jacobsen{at}stemcell.lu.se.
Severe and prolonged cytopenias represent a considerable problem in clinical stem cell transplantations. Cytokine-induced ex vivo expansion of hematopoietic stem and progenitor cells has been intensively explored as a mean of accelerating hematopoietic recovery following transplantation, but have so far had limited success. Herein, overexpression of D-type cyclins, promoting G0/G1 to S transition, was investigated as an alternative approach to accelerate myeloid reconstitution following stem cell transplantation. Using retroviral mediated gene transfer, cyclin D2 was overexpressed in murine bone marrow progenitor cells, which at limited doses showed enhanced ability to rescue lethally ablated recipients. Competitive repopulation studies demonstrated that overexpression of cyclin D2 accelerated myeloid reconstitution following transplantation, and in agreement with this, cyclin D2 transduced myeloid progenitors showed an enhanced proliferative response to cytokines in vitro. Furthermore, cyclin D2 overexpressing myeloid progenitors and their progeny were sustained for longer periods in culture, resulting in enhanced and prolonged granulocyte production in vitro. Thus, overexpression of cyclin D2 confers myeloid progenitors with an enhanced proliferative and granulocyte potential, facilitating rapid myeloid engraftment and rescue of lethally ablated recipients.
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