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 Blood, 15 September 2007, Vol. 110, No. 6, pp. 1779-1787.
Prepublished online as a Blood First Edition Paper on May 11, 2007; DOI 10.1182/blood-2006-11-053710.

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GENE THERAPY

Stable differentiation and clonality of murine long-term hematopoiesis after extended reduced-intensity selection for MGMT P140K transgene expression

Claudia R. Ball1,3, Ingo H. Pilz2,3, Manfred Schmidt1,2,4, Sylvia Fessler1, David A. Williams5, Christof von Kalle1,5, and Hanno Glimm1,2,4

1 National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; 2 Institute of Molecular Medicine and Cell Research, 3 Faculty of Biology, 4 Department of Internal Medicine I, Albert-Ludwigs-University, Freiburg, Germany; 5 Experimental Hematology Molecular and Gene Therapy Program, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center, OH

Efficient in vivo selection increases survival of gene-corrected hematopoietic stem cells (HSCs) and protects hematopoiesis, even if initial gene transfer efficiency is low. Moreover, selection of a limited number of transduced HSCs lowers the number of cell clones at risk of gene activation by insertional mutagenesis. However, a limited clonal repertoire greatly increases the proliferation stress of each individual clone. Therefore, understanding the impact of in vivo selection on proliferation and lineage differentiation of stem-cell clones is essential for its clinical use. We established minimal cell and drug dosage requirements for selection of P140K mutant O6-methylguanine-DNA-methyltransferase (MGMT P140K)–expressing HSCs and monitored their differentiation potential and clonality under long-term selective stress. Up to 17 administrations of O6-benzylguanine (O6-BG) and 1,3-bis(2-chloroethyl)-1-nitroso-urea (BCNU) did not impair long-term differentiation and proliferation of MGMT P140K–expressing stem-cell clones in mice that underwent serial transplantation and did not lead to clonal exhaustion. Interestingly, not all gene-modified hematopoietic repopulating cell clones were efficiently selectable. Our studies demonstrate that the normal function of murine hematopoietic stem and progenitor cells is not compromised by reduced-intensity long-term in vivo selection, thus underscoring the potential value of MGMT P140K selection for clinical gene therapy.


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