This is a competing renewal application whose overall objective is to define the mechanisms of interferon (IFN)-signaling in malignant cells. IFNs exhibit important antineoplastic properties in vitro and in vivo and are key elements in the immune surveillance against cancer, but the mechanisms by which they generate such effects remain to be defined. We have provided the first evidence that the mTOR signaling cascade is engaged by IFN receptors (IFNRs) and regulates cap-dependent mRNA translation via control of the eukaryotic initiation factor 4E (eIF4E) and the eIF4F complex. Remarkably, our studies have provided evidence for signaling specificity and differential use of mTORC2 complexes by IFNs, as compared to oncogenic signals. Our studies suggest dual regulatory roles for mTORC2 complexes in IFN-signaling, controlling downstream pathways that regulate both transcription and mRNA translation of ISGs. The current proposal is a systematic approach to dissect the functions and roles of these complexes in IFN-signaling and to define their relevance in the generation of the antineoplastic effects of IFNs.
Specific aim 1 will identify upstream IFNR-generated signals that lead to mTORC2 activation and will determine the mechanisms of specificity of mTORC2 engagement by the Type I IFNR. It includes studies to dissect the role of IFNR-associated kinases in the process;studies to define whether differential engagement of distinct Sin1 isoforms accounts for specificity in the IFN-system;and screening efforts to identif novel Rictor- and Sin1-interacting IFN-signaling elements. Specif ic aim 2 will define the mechanisms by which mTORC2 complexes control ISG expression and their roles in the generation of IFN-inhibitory responses in malignant cells. It includes experiments to define the roles of mTORC2 complexes in IFNR-activated signaling cascades that regulate transcriptional activation and mRNA translation of ISGs;experiments on the effects of IFN?-activated mTORC2 complexes on AGC kinases;and studies to dissect the requirement of distinct downstream effector elements of mTOR pathways in the generation of IFN-antiproliferative responses. Specif ic aim 3 will examine the roles of mTOR-dependent signals in the antineoplastic effects of IFNs in Ph (-) myeloproliferative neoplasms (MPNs). JAK2V617F mouse models will be established in AKT -/-, S6K -/- and Pdcd4 -/- KO mice, and the ability of IFN? to induce antileukemic responses in vivo, in the presence or absence of distinct effectors of the pathway, will be assessed. The activation of IFN-dependent mTOR pathways in primary hematopoietic precursors from patients with MPNs in vitro and in vivo will be assessed and correlated with IFN-sensitivity. Altogether, these studies will advance our understanding of the signaling mechanisms controlling generation of IFN-antitumor responses and will provide important information on the events that lead to malignant cell resistance to IFNs. Ultimately, they may form the basis for new approaches to overcome IFN-resistance.

Public Health Relevance

Interferons exhibit important antitumor properties and play key roles in the immune surveillance against cancer, but the precise mechanisms by which they generate their effects remain to be defined. We have identified a novel pathway by which IFNs promote expression of IFN stimulated genes (ISGs), involving mTOR complexes. Our data suggest key roles for mTORC2 complexes in IFN-signaling, controlling mTORC1-dependent events and ultimately regulating cap-dependent mRNA translation via the eukaryotic initiation factor 4E (eIF4E) and the eIF4F complex. Remarkably, we have found evidence for selective, IFN-specific, functions of mTORC2 complexes and involvement and regulatory effects in transcriptional activation of ISGs. The current proposal will dissect and define the role of mTOR signals in the generation of the inhibitory properties of IFNs in myeloproliferative neoplasms (MPNs) and will identify upstream regulatory mechanisms and downstream effectors of the cascade. Studies will be also performed to examine whether defective engagement of mTORC2 elements results in leukemic cell resistance to the effects of IFNs in vitro and in vivo.

National Institute of Health (NIH)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Mccarthy, Susan A
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Beauchamp, Elspeth M; Kosciuczuk, Ewa M; Serrano, Ruth et al. (2015) Direct binding of arsenic trioxide to AMPK and generation of inhibitory effects on acute myeloid leukemia precursors. Mol Cancer Ther 14:202-12
Eckerdt, Frank; Beauchamp, Elspeth; Bell, Jonathan et al. (2014) Regulatory effects of a Mnk2-eIF4E feedback loop during mTORC1 targeting of human medulloblastoma cells. Oncotarget 5:8442-51
Wu, Edward J; Goussetis, Dennis J; Beauchamp, Elspeth et al. (2014) Resveratrol enhances the suppressive effects of arsenic trioxide on primitive leukemic progenitors. Cancer Biol Ther 15:473-8
Burke, J D; Platanias, L C; Fish, E N (2014) Beta interferon regulation of glucose metabolism is PI3K/Akt dependent and important for antiviral activity against coxsackievirus B3. J Virol 88:3485-95
Fish, Eleanor N; Platanias, Leonidas C (2014) Interferon receptor signaling in malignancy: a network of cellular pathways defining biological outcomes. Mol Cancer Res 12:1691-703
Kroczynska, Barbara; Mehrotra, Swarna; Arslan, Ahmet Dirim et al. (2014) Regulation of interferon-dependent mRNA translation of target genes. J Interferon Cytokine Res 34:289-96
Kaur, Surinder; Kroczynska, Barbara; Sharma, Bhumika et al. (2014) Critical roles for Rictor/Sin1 complexes in interferon-dependent gene transcription and generation of antiproliferative responses. J Biol Chem 289:6581-91
Keeton, Erika K; McEachern, Kristen; Dillman, Keith S et al. (2014) AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia. Blood 123:905-13
Altman, Jessica K; Szilard, Amy; Goussetis, Dennis J et al. (2014) Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2/mTORC1 targeting. Clin Cancer Res 20:2400-9
Kroczynska, Barbara; Mehrotra, Swarna; Majchrzak-Kita, Beata et al. (2014) Regulatory effects of SKAR in interferon ? signaling and its role in the generation of type I IFN responses. Proc Natl Acad Sci U S A 111:11377-82

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