Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

Abstract

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,...

Interferon Alpha Subtype-Specific Suppression of HIV-1 InfectionIn Vivo

“…It is becoming apparent that subtle differences in the amino acid sequences of IFN-␣ subtypes can produce a significant effect on the binding affinity for the IFN-␣/␤ receptor, downstream signaling events, and antiviral efficacy (2)(3)(4)(5)82). Given that rhesus macaque IFN-␣2 sequences compared to human and SM/AGM IFN-␣2 are only 92 and 98% identical, respectively, future studies in macaques should consider using species-specific IFNs rather than human IFNs (83).…”

“…Interestingly, human IFN-␣ is not a single entity, but rather, the products of a multigene family encoding 12 IFN-␣ subtypes (1), all of which bind to the IFN-␣/␤ receptor. Each subtype binds the receptor using distinctive contacts (2), thereby eliciting distinct signaling events (3,4) and variable biological outcomes (5). While the unique affinity of the subtypes for each receptor subunit seems to contribute to differential downstream signaling, there appear to be additional factors influencing the unique outcomes elicited by individual subtypes that are currently not fully understood.…”

Curcumin Suppresses Janus Kinase-STAT Inflammatory Signaling through Activation of Src Homology 2 Domain-Containing Tyrosine Phosphatase 2 in Brain Microglia

“…Specific subtypes of JAK and STAT molecules mediate different signals, resulting in specificity of responses (15,16). The binding of a ligand to its receptor induces assembly of an active receptor complex and subsequent phosphorylation of the receptor-associated JAKs (JAK1, JAK2, JAK3) and tyrosine kinase 2.…”

Biomarkers and mediators in systemic lupus erythematosus : IFNα versus the CRP response, and evaluation of suPAR and anti-dsDNA antibody assays

“…and 21), IFNα8 and IFNα2 showed the highest affinity for IFNAR2, whereas IFNα1 had relatively high IFNAR1 affinity and therefore stronger antiproliferative effects [112]. Alternative dimer formations of STAT ( Figure 5, pathways to the right) can possibly explain the various effects of IFNα-IFNAR interactions [113,114]. The overall biological outcome of IFNα signaling may therefore be determined by cell type, STAT expression levels/patterns and the specific mixture of IFNα subtypes present in the environment [113].…”