Epigenetic priming: the target?

and inflammatory conditions including immune-mediated bone marrow failure and the often-profound pancytopenia seen in those patients treated with interferons. Apparently , IFN-␣ and IFN-␥ have similar effects in this Irgm1 pathway (Margaret Goodell, personal communication, June 2011). These observations have immediate clinical consequences as an easier-to-tolerate pegy-lated form of IFN-␣ has been shown to induce complete clinical remission in a majority of patients with polycythemia vera 1 and essential thrombocythemia 11 and to decrease JAK2 al-lelic burden and, in some cases, decrease the proportion of cytogenetic abnormality. Previously , Liu and coworkers 2 have also shown that IFN-␣ is the only shown agent that can convert clonal polycythemia vera myeloid he-matopoiesis to polyclonal hematopoiesis. As presented at the 2010 American Society of Hematology Meeting, pegylated IFN-␣ in some patients selectively decreased the JAK2V617F allelic burden without rescuing nonclonal hematopoiesis in some patients, yet in other patients, it resuscitates normal hema-topoietic cells with a conversion of polyclonal cells without much change of JAK2V617F allelic burden. Whether these observations could be explained solely by the effect on stem cells is not clear, as alternate mechanisms, or a combination of other mechanisms (such as stimulation of so-called testicular cancer antigens and the immune response against them) as has been shown in chronic myelocytic leukemia and more recently in polycythemia vera, 12 or direct suppression of JAK2V617F-bearing hemato-poietic progenitors 13 remains to be determined. It also remains to be shown if the inter-feron effect on the stem cells selectively stimulates clonal JAK2V617F Ϫ , stem cell of JAK2V617F ϩ subclone, or normal dormant hematopoietic cells (figure panel B). Finally, the salutary effect of interferon therapy, which has been used in clinical practice without a full understanding of its mechanisms , is becoming clearer. One can hope that the direct targeting of the control mechanisms that protect stem cells from their depletion without other systemic detrimental effects of interferon, such as depression or promotion of autoimmune complications, could be transferred to a more targeted clinical benefit. Conflict-of-interest disclosure: The author declares no competing financial interests. ■ REFERENCES 1. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Prchal JT. Discrimination of polycythemias and thrombo-cytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. Weksberg DC, et al. Irgm1 protects hematopoietic stem cells by negative regulation …