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Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity
Catherine Matte-Martone, … , John T. Harty, Warren D. Shlomchik
Catherine Matte-Martone, … , John T. Harty, Warren D. Shlomchik
Published June 12, 2017
Citation Information: J Clin Invest. 2017;127(7):2765-2776. https://doi.org/10.1172/JCI85736.
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Research Article Immunology Transplantation

Differential requirements for myeloid leukemia IFN-γ conditioning determine graft-versus-leukemia resistance and sensitivity

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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.

Authors

Catherine Matte-Martone, Jinling Liu, Meng Zhou, Maria Chikina, Douglas R. Green, John T. Harty, Warren D. Shlomchik

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Figure 7

CD4 and CD8-mediated GVL require intact T cell perforin or leukemia FADD/RIPK3, and T cell–derived IFN-γ alone is insufficient for GVL.

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CD4 and CD8-mediated GVL require intact T cell perforin or leukemia FADD...
Irradiated B6 mice were reconstituted with BALB/c BM and B6 Fadd–/– Ripk3–/– (DKO) or control B6 Fadd+/– Ripk3+/– mBC-CML (WT) with no BALB/c T cells or with WT or perforin–/– CD8 cells (A) or CD4 cells (B). Data show survival rates from 1 of 2 similar experiments with 10 mice per group. P < 0.0003, comparing any WT or DKO BM-alone group with any WT T cell group. P > 0.07, comparing DKO BM-alone versus perforin–/– CD4 or CD8 groups. P values determined by 2-tailed Mann-Whitney U test.
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