Until recently, the mainstay of Chronic Myelogenous Leukemia (CML) therapy was Interferon (IFN) alpha, which in a minority of patients induces long lasting cytogenetic remission. While the exact mechanism of action of IFN alpha in CML is still obscure, it is clear that the clinical response to IFN alpha correlates with immune system reactivity against leukemic clones. As minimal molecular disease often persists despite the use of imatinib and new Bcr-Abl inhibitors, immunotherapy remains an appealing adjunct to molecularly targeted inhibitors in CML therapy. We have shown that IRF8/ICSBP (Interferon Consensus Sequence Binding Protein) expression in Bcr-Abl transformed cells prevents their capacity to form a lethal leukemia when injected into mice, and that this protection is mediated by a long-lasting and potent CD8+ response against unknown epitopes on the leukemic cells. We hypothesized that the protection mediated by IRF8/ICSBP might be related to the anti-leukemic effects of IFN alpha. We now find that Type I IFNs like IFN alpha regulate IRF8/ICSBP expression in mouse and human cells and in Bcr-Abl transformed cells. Furthermore, type I IFNs can substitute for ICSBP in inducing the anti-leukemic immunity against Bcr-Abl transformed cells. Transcriptional profiling of cells expressing ICSBP, Bcr-Abl, or both ICSBP and Bcr-Abl identified two chemokines, CCL6 and CCL9, which were associated with the immune protection induced by IRF8/ICSBP expression. Type I IFNs and IRF8/ICSBP induce the expression of these chemokines in cells transformed with Bcr-Abl. RNAi-mediated inhibition experiments in our mouse model of CML show that these chemokines are required for the IRF8/ICSBP-mediated CD8+ anti-leukemic response to the Bcr-Abl transformed cells, suggesting that these chemokines could be exploited for immunotherapy in combination with existing Bcr-Abl peptide vaccines.
Disclosure: No relevant conflicts of interest to declare.