title: In vivo selection of genetically modified erythroid cells using a jak2-based cell growth switch.
abstract: Cell-based therapies have potential widespread applications in clinical medicine, and methods for controlling the fate of transplanted cells are needed. We have previously described a means for directing the growth of genetically modified cells in vivo using a derivative of the thrombopoietin receptor, mpl, that is reversibly activated by a drug called a chemical inducer of dimerization (CID). Since Jak2 participates in signaling from a number of different cytokine receptors (including mpl), we tested whether direct activation of the JH1 domain of Jak2 would broaden the repertoire of hematopoietic lineages responsive to the CID. While the engineered Jak2 induced a significant rise in genetically modified red cells, as we have observed previously with mpl, it lacked mpl's ability to expand genetically modified platelets and failed to expand genetically modified granulocytes, B cells, or T cells. These findings identify a signaling molecule other than mpl that can function as a cell growth switch in vivo and demonstrate that signaling molecules used for in vivo selection need not be confined to receptors. The erythroid-restricted growth response suggests that CID-activated Jak2 may be well suited to gene therapy applications in sickle cell anemia or beta-thalassemia.
authors.affiliation: Division of Hematology, Department of Medicine, Mail Stop 357710, K260 Health Sciences Building, University of Washington, Seattle, WA 98195, USA.
authors.forename: Shengming
authors.initials: S
authors.lastname: Zhao
authors.forename: Michael A
authors.initials: MA
authors.lastname: Weinreich
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.forename: Robert E
authors.initials: RE
authors.lastname: Richard
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Blau
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D041905:Erythroid Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053614:Janus Kinase 2; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000378:metabolism*; D053628:Receptors, Thrombopoietin; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013926:Thrombopoietin / Q000378:metabolism
chemical_list: C463061:AP20187; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; C084881:flt3 ligand protein; C082218:MPL protein, human; D013926:Thrombopoietin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D016559:Tacrolimus