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

J Clin Invest. 2017 Jun 30;127(7):2765-2776. doi: 10.1172/JCI85736. Epub 2017 Jun 12.


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.

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Graft vs Leukemia Effect / drug effects*
  • Graft vs Leukemia Effect / genetics
  • Graft vs Leukemia Effect / immunology
  • Humans
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology*
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / genetics
  • Leukemia, Myeloid / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / immunology
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / pathology


  • IFNG protein, mouse
  • Interferon-gamma