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Small-Molecule-Directed Mpl Signaling Can Complement Growth Factors to Selectively Expand Genetically Modified Cord Blood Cells

Division of Hematology, Department of Medicine,University of Washington School of Medicine, Seattle, Washington

Key Words. Gene therapy • Hematopoiesis • Cytokines • Thrombopoietin receptor

C. Anthony Blau, M.D., Mailstop 357710, Health Sciences Building, University of Washington, Seattle, Washington 98195, USA. Telephone: 206-685-6873; Fax: 206-543-3560; e-mail:
tblau{at}u.washington.edu

Efforts toward achieving gene therapy for blood disorders are plagued by low rates of gene transfer into hemopoietic stem cells. Recent studies suggest that this obstacle can be circumvented using selection. One way to achieve selection employs genes that encode receptor-bearing fusion proteins capable of inducing cell growth in response to drugs called chemical inducers of dimerization (CIDs). We have previously shown that genetically modified marrow cells from mice can proliferate for up to a year in culture in response to CID-initiated signals arising from the thrombopoietin receptor (mpl). The sustained growth observed in mouse hemopoietic cells results from an mpl-induced self-renewal of multipotential hemopoietic progenitor cells. In contrast, human hemopoietic cells proliferate only transiently in response to the mpl signal (from differentiation of transduced erythroid and megakaryocytic progenitors), while human myeloid progenitors fail to respond. Here, we show that myeloid progenitors from human cord blood can be induced to proliferate and/or differentiate in response to the mpl signal by providing additional signals via a combination of growth factors. These findings are relevant for the eventual clinical application of CID-regulated cell therapy.

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