Journal article
Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity
The Journal of clinical investigation, Vol.127(7), pp.2765-2776
06/30/2017
DOI: 10.1172/JCI85736
PMCID: PMC5490746
PMID: 28604385
Abstract
The graft-versus-leukemia (GVL) effect in allogeneic hematopoietic stem cell transplantation (alloSCT) is potent against chronic phase chronic myelogenous leukemia (CP-CML), but blast crisis CML (BC-CML) and acute myeloid leukemias (AML) are GVL resistant. To understand GVL resistance, we studied GVL against mouse models of CP-CML, BC-CML, and AML generated by the transduction of mouse BM with fusion cDNAs derived from human leukemias. Prior work has shown that CD4+ T cell-mediated GVL against CP-CML and BC-CML required intact leukemia MHCII; however, stem cells from both leukemias were MHCII negative. Here, we show that CP-CML, BC-CML, and AML stem cells upregulate MHCII in alloSCT recipients. Using gene-deficient leukemias, we determined that BC-CML and AML MHC upregulation required IFN-γ stimulation, whereas CP-CML MHC upregulation was independent of both the IFN-γ receptor (IFN-γR) and the IFN-α/β receptor IFNAR1. Importantly, IFN-γR-deficient BC-CML and AML were completely resistant to CD4- and CD8-mediated GVL, whereas IFN-γR/IFNAR1 double-deficient CP-CML was fully GVL sensitive. Mouse AML and BC-CML stem cells were MHCI+ without IFN-γ stimulation, suggesting that IFN-γ sensitizes these leukemias to T cell killing by mechanisms other than MHC upregulation. Our studies identify the requirement of IFN-γ stimulation as a mechanism for BC-CML and AML GVL resistance, whereas independence from IFN-γ renders CP-CML more GVL sensitive, even with a lower-level alloimmune response.
Details
- Title: Subtitle
- Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity
- Creators
- Catherine Matte-Martone - Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USAJinling Liu - Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USAMeng Zhou - Department of Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USAMaria Chikina - Department of Computational Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USADouglas R Green - Department of Immunology, St. Jude Children's Research Hospital, Memphis Tennessee, USAJohn T Harty - Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USAWarren D Shlomchik - Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.127(7), pp.2765-2776
- Publisher
- United States
- DOI
- 10.1172/JCI85736
- PMID
- 28604385
- PMCID
- PMC5490746
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- R01 CA169291 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 HL117855 / NHLBI NIH HHS
- Language
- English
- Date published
- 06/30/2017
- Academic Unit
- Pathology
- Record Identifier
- 9984047768202771
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