Interferons and IRF8/ICSBP Stimulate Immune Protection Against BCR/ABL-Induced Leukemia.

Chronic Myeloid Leukemia (CML) results from transformation of hematopoietic stem cells by the BCR/ABL oncoprotein. CML can be effectively treated with the targeted ABL kinase inhibitor Imatinib (STI571; Gleevec), but patients rarely achieve molecular remission by sensitive PCR methods, and drug resistance limits the durability of drug response. A significant minority of patients treated with Interferon (IFN) alpha achieve complete cytogenetic remission, and response is correlated with immune reactivity against leukemic clones. This suggests that IFN-induced immunotherapy might be an important adjunct to Gleevec, thus prompting us to investigate immunoprotective mechanisms. We have shown previously that ectopic expression of Interferon Regulatory factor 8 (IRF8, also called ICSBP) can stimulate a potent CD8+ cytotoxic anti-leukemia response in a murine model of BCR/ABL-induced leukemia (Deng and Daley, Blood 97;3491, 2001). In transcriptional profiling experiments with cells that overexpress IRF8/ICSBP, we detected increased expression of IFN alpha and beta. To test whether IFN alpha or beta can mediate the same protective immune-response as IRF8/ICSBP, we co-injected BCR/ABL-transformed BaF3 cells together with non-transformed BaF3 cells engineered to overexpress IFN alpha or beta. Expression of IFN alpha or beta in trans protected mice from developing leukemia. Control constructs in which IFN alpha or beta were cloned in the anti-sense orientation failed to confer protection, confirming the importance of IFN alpha or beta expression. Importantly, IRF8/ICSBP expression is protective against cells transformed by Gleevec-resistant mutant BCR/ABL proteins (T315I and L248R). Our data suggest that IFNs are functionally equivalent to IRF8/ICSBP in conferring a vaccine-like anti-leukemic immune effect in our model, and may act through an autoregulatory loop involving IRF8/ICSBP. Defining the precise epitopes targeted by the IFN/ICSBP-induced immune response may enable immunotherapy in human CML patients.