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      Modulation of phospho-proteins by interferon-alpha and valproic acid in acute myeloid leukemia

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          Abstract

          Purpose

          Valproic acid (VPA) is suggested to be therapeutically beneficial in combination with interferon-alpha (IFNα) in various cancers. Therefore, we examined IFNα and VPA alone and in combinations in selected AML models, examining immune regulators and intracellular signaling mechanisms involved in phospho-proteomics.

          Methods

          The anti-leukemic effects of IFNα and VPA were examined in vitro and in vivo. We mapped the in vitro phosphoprotein modulation by IFNα-2b and human IFNα-Le in MOLM-13 cells by IMAC/2D DIGE/MS analysis and phospho-flow cytometry, and in primary healthy and AML patient-derived PBMCs by CyTOF. In vivo, IFNα-Le and VPA efficacy were investigated in the immunodeficient NOD/Scid IL2γ−/− MOLM-13 Luc+ mouse model and the syngeneic immunocompetent BNML rat model.

          Results

          IFNα-2b and IFNα-Le differed in the modulation of phospho-proteins involved in protein folding, cell stress, cell death and p-STAT6 Y641, whereas VPA and IFNα-Le shared signaling pathways involving phosphorylation of Akt (T308), ERK1/2 (T202/T204), p38 (T180/Y182), and p53 (S15). Both IFNα compounds induced apoptosis synergistically with VPA in vitro. However, in vivo, VPA monotherapy increased survival, but no benefit was observed by IFNα-Le treatment. CyTOF analysis of primary human PBMCs indicated that lack of immune-cell activation could be a reason for the absence of response to IFNα in the animal models investigated.

          Conclusions

          IFNα-2b and IFNα-Le showed potent and synergistic anti-leukemic effects with VPA in vitro but not in leukemic mouse and rat models in vivo. The absence of IFNα immune activation in lymphocyte subsets may potentially explain the limited in vivo anti-leukemic effect of IFNα-monotherapy in AML.

          Electronic supplementary material

          The online version of this article (10.1007/s00432-019-02931-1) contains supplementary material, which is available to authorized users.

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          Most cited references45

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          Fluorescent cell barcoding in flow cytometry allows high-throughput drug screening and signaling profiling.

          Flow cytometry allows high-content, multiparameter analysis of single cells, making it a promising tool for drug discovery and profiling of intracellular signaling. To add high-throughput capacity to flow cytometry, we developed a cell-based multiplexing technique called fluorescent cell barcoding (FCB). In FCB, each sample is labeled with a different signature, or barcode, of fluorescence intensity and emission wavelengths, and mixed with other samples before antibody staining and analysis by flow cytometry. Using three FCB fluorophores, we were able to barcode and combine entire 96-well plates, reducing antibody consumption 100-fold and acquisition time to 5-15 min per plate. Using FCB and phospho-specific flow cytometry, we screened a small-molecule library for inhibitors of T cell-receptor and cytokine signaling, simultaneously determining compound efficacy and selectivity. We also analyzed IFN-gamma signaling in multiple cell types from primary mouse splenocytes, revealing differences in sensitivity and kinetics between B cells, CD4+ and CD4- T cells and CD11b-hi cells.
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            Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype.

            To investigate the prognostic value of various cytogenetic components of a complex karyotype in acute myeloid leukemia (AML). Cytogenetics and overall survival (OS) were analyzed in 1,975 AML patients age 15 to 60 years. Besides AML with normal cytogenetics (CN) and core binding factor (CBF) abnormalities, we distinguished 733 patients with cytogenetic abnormalities. Among the latter subgroup, loss of a single chromosome (n = 109) conferred negative prognostic impact (4-year OS, 12%; poor outcome). Loss of chromosome 7 was most common, but outcome of AML patients with single monosomy -7 (n = 63; 4-year OS, 13%) and other single autosomal monosomies (n = 46; 4-year OS, 12%) did not differ. Structural chromosomal abnormalities influenced prognosis only in association with a single autosomal monosomy (4-year OS, 4% for very poor v 24% for poor). We derived a monosomal karyotype (MK) as a predictor for very poor prognosis of AML that refers to two or more distinct autosomal chromosome monosomies (n = 116; 4-year OS, 3%) or one single autosomal monosomy in the presence of structural abnormalities (n = 68; 4-year OS, 4%). In direct comparisons, MK provides significantly better prognostic prediction than the traditionally defined complex karyotype, which considers any three or more or five or more clonal cytogenetic abnormalities, and also than various individual specific cytogenetic abnormalities (eg, del[5q], inv[3]/t[3;3]) associated with very poor outcome. MK enables (in addition to CN and CBF) the prognostic classification of two new aggregates of cytogenetically abnormal AML, the unfavorable risk MK-negative category (4-year OS, 26% +/- 2%) and the highly unfavorable risk MK-positive category (4-year OS, 4% +/- 1%).
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              Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma.

              Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial. In all, 1,256 patients with resected stage III melanoma were randomly assigned to observation (n = 629) or PEG-IFN-α-2b (n = 627) for an intended duration of 5 years. Stratification factors were microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumor thickness, sex, and center. Recurrence-free survival (RFS; primary end point), distant metastasis-free survival (DMFS), and overall survival (OS) were analyzed for the intent-to-treat population. At 7.6 years median follow-up, 384 recurrences or deaths had occurred with PEG-IFN-α-2b versus 406 in the observation group (hazard ratio [HR], 0.87; 95% CI, 0.76 to 1.00; P = .055); 7-year RFS rate was 39.1% versus 34.6%. There was no difference in OS (P = .57). In stage III-N1 ulcerated melanoma, RFS (HR, 0.72; 99% CI, 0.46 to 1.13; P = .06), DMFS (HR, 0.65; 99% CI, 0.41 to 1.04; P = .02), and OS (HR, 0.59; 99% CI, 0.35 to 0.97; P = .006) were prolonged with PEG-IFN-α-2b. PEG-IFN-α-2b was discontinued for toxicity in 37% of patients. Adjuvant PEG-IFN-α-2b for stage III melanoma had a positive impact on RFS, which was marginally significant and slightly diminished versus the benefit seen at prior follow-up (median, 3.8 years). No significant increase in DMFS or OS was noted in the overall population. Patients with ulcerated melanoma and lower disease burden had the greatest benefit.
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                Author and article information

                Contributors
                +4755972968 , bjorn.gjertsen@uib.no
                Journal
                J Cancer Res Clin Oncol
                J. Cancer Res. Clin. Oncol
                Journal of Cancer Research and Clinical Oncology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0171-5216
                1432-1335
                20 May 2019
                20 May 2019
                2019
                : 145
                : 7
                : 1729-1749
                Affiliations
                [1 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, Precision Oncology Research Group, , University of Bergen, ; P.O Box 7804, 5020 Bergen, Norway
                [2 ]ISNI 0000 0000 9753 1393, GRID grid.412008.f, Department of Internal Medicine, Hematology Section, , Haukeland University Hospital, ; Bergen, Norway
                [3 ]GRID grid.477239.c, Department of Biomedical Laboratory Sciences and Chemical Engineering, , Bergen University College, ; Bergen, Norway
                [4 ]ISNI 0000 0004 1936 7443, GRID grid.7914.b, Department of Clinical Science, Faculty of Medicine and Dentistry, , University of Bergen, ; Bergen, Norway
                Author information
                http://orcid.org/0000-0001-9358-9704
                Article
                2931
                10.1007/s00432-019-02931-1
                6571093
                31111215
                eecbb7fd-cc4f-41af-82b7-0861f2b1cbf6
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 11 May 2018
                : 7 May 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100008730, Kreftforeningen;
                Award ID: 104712
                Award ID: 145268
                Award ID: 145269
                Award ID: 163424
                Award Recipient :
                Funded by: Trond Mohn Foundation
                Award ID: _
                Award Recipient :
                Funded by: Helse Vest (NO)
                Award ID: 912160
                Award Recipient :
                Categories
                Original Article – Cancer Research
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2019

                Oncology & Radiotherapy
                aml,ifnα,vpa,phospho-flow,cytof,phosphoproteome
                Oncology & Radiotherapy
                aml, ifnα, vpa, phospho-flow, cytof, phosphoproteome

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