Initial expression of interferon alpha receptor 2 (IFNAR2) on CD34‐positive cells and its down‐regulation correlate with clinical response to interferon therapy in chronic myelogenous leukemia

Ito, Kinro; Tanaka, Hideo; Ito, Takuo; Sultana, Tanvira Afroze; Kyo, Taiichi; Imanaka, Fumio; Ohmoto, Yasukazu; Kimura, Akiro

doi:10.1111/j.1600-0609.2004.00275.x

Cited by 25 publications

(13 citation statements)

References 52 publications

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“…43 Furthermore, the initial pretreatment mRNA and protein levels of IFNAR2c were predictive of outcome of IFN␣ therapy in CML patients. 44,45 Besides these mechanistic insights, the significance of these findings may be clinically relevant for efforts to restore the sensitivity of CML cells to IFN␣. This purported mechanism provides a rationale for a strategy using suboptimal doses of TKI before IFN␣ delivery to increase the sensitivity of the chronic phase CML patients to IFN␣.…”

Section: Discussionmentioning

confidence: 99%

Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Bhattacharya¹,

Zheng²,

Tzimas³

et al. 2011

Blood

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IntroductionPatients with chronic myeloid leukemia (CML) harbor a specific translocation t(9;22)(q34;q11), the Philadelphia chromosome, resulting in the expression of a constitutively active protein tyrosine kinase Bcr-abl that is essential for the hematopoietic cell transformation. 1 This kinase exerts its oncogenic function by activating a cascade of intracellular signaling pathways that lead to increased cell survival and proliferation and limited dependence on growth factors. Among these pathways are those that mediate activation of PI3K-Akt, MAPK, and protein kinase (PK)C/PKD signaling cascades that generally stimulate cell proliferation and survival. 2,3 The Bcr-abl inhibitor imatinib mesylate (IM) has replaced interferon IFN␣ as the standard of care for patients with newly diagnosed chronic myeloid leukemia (CML) because of higher response frequency, substantially superior molecular and cytogenetic responses, lesser toxicity, and better survival. [4][5][6][7] Yet, although rapidly killing differentiated CML cells, IM is less efficient against more primitive leukemic stem cells and early progenitor cells. 8,9 Thus, patients receiving IM are not cured and require life-long treatment that is often compromised by resistance to IM because of mutations in Bcr-abl tyrosine kinase. 7,10 The ability of the second and third generation of tyrosine kinase inhibitors (TKIs; eg, dasatinib that might be active against mutant kinases) to eradicate quiescent early CML progenitors remains to be determined. 11 It is plausible that a combination of Bcr-abl inhibitors and the agents targeting the leukemic stem cell population might be required to eradicate the disease in CML patients.Recent evidence suggests that leukemic stem cells might undergo terminal differentiation in response to IFN␣, 12 a cytokine known to produce a curative effect in a small subset of patients (reviewed in Kujawski and Talpaz 13 ). Although these results, along with reports on several cases of successful treatment with IFN␣ after a course of IM (or vice versa), 14,15 provide new enthusiasm for the reintroduction of IFN␣ into the management of CML, 13 the molecular mechanisms that underlie the rationale for combining Bcr-abl inhibitors and IFN␣ remain to be delineated. Cellular responses to IFN␣ are mediated by the cell surface type I IFN receptor that consists of the interferon-␣/␤ receptor (IFNAR)1 and IFNAR2 chains. Ligand-stimulated dimerization of these chains leads to the activation of Janus kinase (JAK) family members JAK1 and TYK2. JAK1 and TYK2 phosphorylate signal transducers and activators of transcription (STAT) family proteins at specific tyrosine residues. Tyrosine phosphorylation of STAT1 and STAT2 along with subsequent recruitment of p48/IRF9 leads to the formation of a potent transcription factor that transactivates IFN-stimulated genes and contribute to the antiproliferative effects of IFN␣ (for reviews, see [16][17][18][19] ).A better understanding of molecular interactions between IFN␣-and Bcr-abl-induced signaling pathways is requ...

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Section: Discussionmentioning

confidence: 99%

Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Bhattacharya¹,

Zheng²,

Tzimas³

et al. 2011

Blood

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“…It remains to be seen whether studying additional cell lines with various levels of receptor numbers and different ratios between the two subunits will reveal a different profile of reduction in activity upon their downregulation. In this context, studies in hepatocellular carcinoma and CD34-positive cells suggested that also in those systems, surface receptor concentration is important to the efficiency of interferon as a cancer drug (7,12).…”

Section: Discussionmentioning

confidence: 99%

“…It was shown that a decrease in cell surface concentration of one or both of the receptor subunits reduces cell sensitivity and alters signaling (5,25,26,43,49). In addition, a clear correlation between the efficiency of interferon as an antiviral drug or a cancer drug and surface receptor concentration was suggested (7,12,27,49). Using stably transfected cells, it was shown that an increased number of receptors resulted in an overall elevated sensitivity for IFNs, accompanied by a de-crease in interferon differential activity between the low-and high-affinity cytokines IFN-␣ and -␤ (29).…”

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confidence: 99%

Stochastic Receptor Expression Determines Cell Fate upon Interferon Treatment

Levin

Harari

Schreiber

2011

Molecular and Cellular Biology

114

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Type I interferons trigger diverse biological effects by binding a common receptor, composed of IFNAR1 and IFNAR2. Intriguingly, while the activation of an antiviral state is common to all cells, antiproliferative activity and apoptosis affect only part of the population, even when cells are stimulated with saturating interferon concentrations. Manipulating receptor expression by different small interfering RNA (siRNA) concentrations reduced the fraction of responsive cells independent of the interferon used, including a newly generated, extremely tight-binding variant. Reduced receptor numbers increased 50% effective concentrations (EC 50 s) for alpha interferon 2 (IFN-␣2) but not for the tight-binding variant. A correlation between receptor numbers, STAT activation, and gene induction is observed. Our data suggest that for a given cell, the response is binary (؉/؊) and dependent on the stochastic expression levels of the receptors on an individual cell. A low number of receptors suffices for antiviral response and is thus a robust feature common to all cells. Conversely, a high number of receptors is required for antiproliferative activity, which allows for fine-tuning on a single-cell level.Type I interferons (IFNs) form a class of cytokines capable of mediating antiviral, growth inhibitory, and immunoregulatory activities (10,36,46). Consisting of 18 members in humans (32), all IFNs induce their biological activities through binding to the same receptor complex, composed of the two transmembrane proteins IFNAR1 and IFNAR2 (1). Upon formation of the ternary complex, the interferon signal is transduced through receptor-associated Janus kinases (JAK), which activate the signal transducers and activators of transcription (STAT) proteins. These, in turn, form homo-and heterodimers that translocate to the nucleus to promote the expression of interferon-stimulated genes (ISGs) (45).Despite their common biological activities and sequence homologies, type I IFNs are not redundant but rather induce their activities differentially (9, 41). These differences take effect in various ways, most notably in the antiviral (AV) and antiproliferative (AP) potencies of interferon subtypes (16,33) and in their abilities to induce different gene expression patterns (11,14,38,48). The AP activities of IFNs are a result of both apoptosis and cell cycle arrest (17,20,40). A profound example for differential activity is the substantially higher AP response induced by beta interferon (IFN-␤) than by 14,21,41). However, it should be noted that most of the differences between IFN-␣2 and IFN-␤ are quantitative and not qualitative; thus, higher IFN-␣2 concentrations mimic most IFN-␤ activities.IFNAR1 and IFNAR2 receptor subunits make distinct contributions to interferon binding, as IFNAR1 binds IFN-␣ with micromolar affinities, while the IFNAR2 subunit binds at nanomolar affinities (6). Nevertheless, the activation of both receptors is necessary to induce the interferon signal (3, 23).Mutagenesis studies have shown that the binding sites f...

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“…51 CML and PV CD34 ϩ cells are more sensitive to the inhibitory effects of IFN␣ than normal HPCs. 49,52 CML CD34 ϩ cells are characterized by greater expression of IFNAR2 but lower expression of IFNAR1. 52 The greater degree of expression of IFNAR2 by CML CD34 ϩ cells has been shown to correlate with a clinical response to IFN␣.…”

Section: Interferon Suppresses the Proliferation Of Hematopoietic Promentioning

confidence: 99%

“…49,52 CML CD34 ϩ cells are characterized by greater expression of IFNAR2 but lower expression of IFNAR1. 52 The greater degree of expression of IFNAR2 by CML CD34 ϩ cells has been shown to correlate with a clinical response to IFN␣. 52 Peschel and coworkers have also reported that the myelosuppressive effects of IFN␣ could also be in part attributed to the inhibition of the paracrine production of several stimulatory hematopoietic growth factors including GM-CSF and IL-11 and inhibition of the production of IL-1 receptor antagonist by marrow stromal cells.…”

Section: Interferon Suppresses the Proliferation Of Hematopoietic Promentioning

confidence: 99%

The renaissance of interferon therapy for the treatment of myeloid malignancies

Kiladjian

Mesa

Hoffman

2011

Blood

176

140

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Initial expression of interferon alpha receptor 2 (IFNAR2) on CD34‐positive cells and its down‐regulation correlate with clinical response to interferon therapy in chronic myelogenous leukemia

Cited by 25 publications

References 52 publications

Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Stochastic Receptor Expression Determines Cell Fate upon Interferon Treatment

The renaissance of interferon therapy for the treatment of myeloid malignancies

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