Modulating erythrocyte chimerism in a mouse model of pyruvate kinase deficiency.
In vivo selection may provide a means to increase the relative number of cells of donor origin in recipients with hemopoietic chimerism. We have tested whether in vivo selection using chemical inducers of dimerization (CIDs) can direct the expansion of transduced normal donor erythrocytes in recipients with chimerism using a mouse model of pyruvate kinase deficiency. Marrow cells from normal CBA/N mice were transduced with a vector (F36Vmpl(GFP)) that promotes cell growth in the presence of CIDs. Transduced cells were then transplanted into minimally conditioned, pyruvate kinase-deficient recipients (CBA-Pk-1(slc)/Pk-1(slc)) to establish stable chimerism. CID administration resulted in expansion of normal donor erythrocytes and improvement of the anemia. The preferential expansion of normal erythrocytes also resulted in a decrease in erythropoietin levels, reducing the drive for production of pyruvate kinase-deficient red blood cells. CID-mediated expansion of genetically modified erythrocytes could prove a useful adjunct to transplantation methods that achieve erythroid chimerism.
Department of Medicine, Mailstop 357710, Health Sciences Building, University of Washington, Seattle, WA 98195, USA. rrichard@u.washington.edu
Robert E
RE
Richard
Michael
M
Weinreich
Kai-Hsin
KH
Chang
Jessica
J
Ieremia
Mary M
MM
Stevenson
C Anthony
CA
Blau
D000740:Anemia / Q000209:etiology / Q000628:therapy; D000818:Animals; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000032:analysis; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D011770:Pyruvate Kinase / Q000172:deficiency* / Q000235:genetics*; D033581:Stem Cell Transplantation; D013997:Time Factors; D018183:Transplantation Chimera
D008164:Luminescent Proteins; D004921:Erythropoietin; D049452:Green Fluorescent Proteins; D011770:Pyruvate Kinase