title: Distinct graft-versus-leukemic stem cell effects of early or delayed donor leukocyte infusions in a mouse chronic myeloid leukemia model.
abstract: Among hematologic neoplasms, chronic myeloid leukemia (CML) is exquisitely sensitive to graft-versus-leukemia (GVL) because patients relapsing after allogeneic hematopoietic stem-cell transplantation (alloHSCT) can be cured by donor leukocyte infusion (DLI); however, the cellular mechanisms and strategies to separate GVL from GVHD are unclear. We used a BCR-ABL1 transduction/transplantation mouse model to study the mechanisms of DLI in MHC-matched, minor histocompatibility antigen-mismatched allogeneic chimeras with CML-like leukemia, in which DLI can be administered at the time of transplantation (early) or after recovery of hematopoiesis (delayed). After early DLI, CML-like leukemia cannot be transferred into immunocompetent secondary recipients as soon as 4 days after primary transplantation, demonstrating that cotransplantation of T lymphocytes blocks the engraftment of BCR-ABL1-transduced stem cells. In contrast, in allogeneic chimeras with established CML-like leukemia, combined treatment with delayed DLI and the kinase inhibitor imatinib eradicates leukemia with minimal GVHD. The GVL effect is directed against minor histocompatibility antigens shared by normal and leukemic stem cells, and is mediated predominantly by CD8+ T cells, with minor contributions from CD5- splenocytes, including natural killer cells. These results define a physiologic model of adoptive immunotherapy of CML that will be useful for investigating the cellular and molecular mechanisms of GVL.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lu
authors.forename: L Cristina
authors.initials: LC
authors.lastname: Gavrilescu
authors.forename: Monica
authors.initials: M
authors.lastname: Betancur
authors.forename: Katherine
authors.initials: K
authors.lastname: Lazarides
authors.forename: Hans
authors.initials: H
authors.lastname: Klingemann
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D016026:Bone Marrow Transplantation; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000401:mortality* / Q000628:therapy*; D017708:Leukocyte Transfusion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D004247:DNA; D016044:Fusion Proteins, bcr-abl
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