IntroductionErythroleukemias represent the highly malignant M6 subtype of acute myeloid leukemia. 1 The J2E cell line, immortalized at the proerythroblast/basophilic erythroblast stage of erythroid development, 2 induces a rapid and fatal erythroleukemia in mice. 3 However, while these cells are immortalized, they are still capable of normal signaling in response to erythropoietin (Epo) stimulation. They maintain all biologic responses to Epo by differentiating biochemically with hemoglobin production and undergoing cellular alterations with a percentage of cells enucleating to form mature reticulocytes. 2,4-7 J2E cells also display increased proliferation and enhanced viability in the absence of serum as a result of Epo stimulation. 2,4,5 Type I interferon (IFN) subtypes are clinically effective in the treatment of disease conditions such as hepatitis, hairy cell leukemia, condyloma acuminatum, multiple sclerosis, and Kaposi sarcoma. [8][9][10][11] These IFNs have also proven effective in the treatment of both myelogenous and metastatic tumors, 12,13 and IFN-␣ has the ability to normalize hemoglobin levels in anemic patients. 14 Subtype diversity for treatment is limited however to human IFN-␣2 (huIFN-␣2) 15 and huIFN- (IFN--1b; IFN--1a).The type I IFNs have been attributed to multiple and diverse functions in the immune response. This multigene family has over 14 IFN-␣ subtypes in humans and 10 IFN-␣ subtypes in mice, with a single IFN- subtype for each. The murine and human IFN gene families are highly analogous. 16 Induced early in the immune response, IFNs stimulate antiviral, 17,18 antiproliferative, 19 and apoptotic activity, 20 as well as have numerous immunomodulatory effects. Type I IFNs regulate dendritic cell major histocompatibility complex (MHC) expression and maturation, 21-24 activate natural killer (NK) cells, 25 induce bystander T-cell proliferation, 26 selectively induce clonal CD8 ϩ T-cell expansion, 26 and skew the immune response to a Th1-like response. 27,28 At the cellular level, type I IFN binds the IFN-␣ receptor 2 (IFNAR2) subunit 29 instigating its association with the IFNAR1 subunit. 30 The preassociated Jak kinases, Jak1 and Tyk2, are subsequently cross-phosphorylated. 31,32 Phosphorylation of signal transducers and activators of transcription 2 (STAT2) occurs, which forms a heterodimer with STAT1 and phosphorylation of the latter. Phosphorylation of other STATs in response to 33 STAT4, 34 STAT5, and STAT6. 35,36 Phosphorylation of STAT4 however is not generally reported in the murine system and is believed to be due to a microsatellite insertion in Stat2. 37 44 Alternatively, IFN-␣ activation of p42 MAPK is essential for cell proliferation. 45 Previously, J2E cells stimulated with mixed murine IFN-␣ (muIFN-␣), IFN-␣1, and IFN-␣4 differed in their antiproliferative capacity, 46 while levels of Epo-induced differentiation were maintained. 47 In this report, we investigated the differential antileukemic properties of a panel of 7 type I IFN subtypes (-␣1, -␣2, -␣4, -␣5, -␣6, -␣9,...