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

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-gamma stimulation, whereas CP-CML MHC upregulation was independent of both the IFN-gamma receptor (IFN-gamma R) and the IFN-alpha/beta receptor IFNAR1. Importantly, IFN-gamma R-deficient BC-CML and AML were completely resistant to CD4- and CD8-mediated GVL, whereas IFN-gamma R/IFNAR1 double-deficient CP-CML was fully GVL sensitive. Mouse AML and BC-CML stem cells were MHCI+ without IFN-beta stimulation, suggesting that IFN-gamma sensitizes these leukemias to T cell killing by mechanisms other than MHC upregulation. Our studies identify the requirement of IFN-gamma stimulation as a mechanism for BC-CML and AML GVL resistance, whereas independence from IFN-gamma renders CP-CML more GVL sensitive, even with a lower-level alloimmune response.