Intra-leukemic interferon signaling suppresses expansion and mediates chemoresistance in human AML
Intra-tumoral heterogeneity can impact the competitive fitness and chemoresistance of individual cancer cells. In acute myeloid leukemia (AML), both genetic and functional heterogeneity contribute to chemoresistance, resulting in relapse after chemotherapy. While the role of cell-extrinsic factors such as interactions with non-leukemic cells has been described for AML relapse, whether interactions between cancer cells affects chemoresistance is not fully known. Here, we demonstrate that a dominant leukemic fraction can suppress the proliferation and expansion of other leukemic cells and that this suppression is reversible. We show that this suppression is mediated in part by both type I and type II intra-leukemic interferon (IFN) signaling and dependent on BST2. Importantly, blocking antibodies to type II IFN receptor activated the cycling of this suppressed cell fraction and sensitized the cells to subsequent chemotherapy treatment. Our findings suggest that interactions between functionally heterogeneous leukemic fractions can affect competitive fitness and treatment response, highlighting IFN signaling as a potential therapeutic target to counter chemoresistance. Overall design: Human cells were engrafted in 4 to 12 week old male or female mice either without irradiation or 2 to 24h after sublethal irradiation (100-200 rad) by intra-venous or intra-femoral injection of 1,000-50,000 iAML cells or 1-5 million AML cells. BFP and mCherry iAML subclones were co-injected (competitive engraftment) or injected alone, or 3 separate pairs of 2 patient sample were co-injected (competitive engraftment) or injected alone. 5 weeks after iAML engraftment or 12-18 weeks after AML cell engraftment, human cells were isolated from crushed whole bone marrow by FACS. For chemotherapy experiments, engrafted iAML or AML samples were sorted from bone marrow aspirates or whole bone marrow 4 weeks after engraftment, 4 weeks after chemotherapy treatment (100 mg/kg cytarabine i.p. 5 days + 1.5 mg/kg doxorubicin i.p. 3 days),  8 weeks after chemotherapy treatment, or at experimental endpoint. For all experiments, total RNA was extracted using QIAGEN miRNeasy micro kit for RNA sequencing by SMART-Seq v4.