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• W1966107562 abstract "The M-phase phosphoprotein 11 (MPP11) gene, a member of the MPP family, encodes a 66-kDa protein and is located on the chromosome 7q22–q31.1 [1,2,3]. It has been documented that MPP11 is capable of forming a heterodimeric complex that associates with ribosomes, acting as a molecular chaperone for nascent polypeptide chains as they exit the ribosome [3,4]. By utilizing serological screening of an expression library (SEREX), Greiner et al. [5,6] first described MPP11 as a cancer testis antigen which is highly upregulated in malignant myeloblasts in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia, but is absent in normal differentiated tissues except for testis tissue. In the current study, we differentially analyzed the humoral immune response against MPP11 in a large cohort of untreated AML patients (n = 126) and in patients receiving an allogeneic stem cell transplantation (allo-SCT; n = 45).In a first set of experiments, we examined the expression of MPP11 in various AML samples and in leukemia cell lines. As documented with confocal laser microscopy (fig. 1a), intracellular FACS staining (fig. 1b) and RT-PCR analyses (fig. 1c), we detected high expression levels of MPP11 in all AML samples (n = 52), independent from the cytogenetic background.For detecting specific anti-MPP11 antibodies, a standard ELISA was performed. Purified recombinant human MPP11 (8 µg/ml) and HIVp24 (8 µg/ml, negative control) were bound to ELISA plates. Responses against HIVp24 (all patients negative) were used as a negative control, and non-specific reactivity was subtracted from each MPP11 optical density (OD) value. To establish cut-off points for anti-MPP11 OD values that distinguished between negative and positive cases, we used different approaches including the mean + 2 SD of the healthy donor samples and the receiver operator characteristic curve [7]. Using these approaches, an OD of 0.150 for both IgG and IgM was chosen as initial cut-off value for determination of positive antibody reactivity for MPP11 and were subsequently applied to healthy donors (n = 70), untreated AML patients and for AML patients treated with an allogeneic SCT. MPP11 protein was generated using a full-length cDNA of human MPP11 cloned into an expression vector under the control of the tac promoter and expressed in Escherichia coli.As depicted in figure 2a, b, the vast majority of untreated AML patients developed significant levels of both anti-MPP11 antibodies. In 103 of 126 (82%) sera of untreated AML patients, IgG-type anti-MPP11 antibodies were detected, whereas in sera of healthy donors, no humoral reactivity against MPP11 was present (fig. 2a). In addition, in nearly one third (29%) of all patient samples, significant titers of IgM antibodies recognizing MPP11 protein could be demonstrated. In contrast, relevant anti-MPP11 antibody titers were absent in sera from healthy donors. In sera of most AML patients receiving an allogeneic SCT, we again recorded high levels of anti-MPP11 antibodies (fig. 2d). These antibodies first appear at least 9 months posttransplantation and were not detectable prior to SCT (fig. 2c). In 28 of 45 patients (62%), we detected both IgG and IgM antibody titers with specificity to MPP11 (table 1). Intriguingly, although 5 patients received immunosuppressive drugs (ciclosporin A) due to treatment of chronic graft-versus-host disease, we were able to detect significant amounts of anti-MPP11 antibodies in their sera (patients No. 11 and 17–20; table 1). We further characterized the humoral anti-MPP11 immune response by analyzing the IgG subclasses. As shown in figure 2e, IgG1 and IgG3 were the predominant subclasses of untreated AML patients, whereas the SCT group predominantly developed IgG1 and IgG2 antibodies against MPP11 (fig. 2e).All patient sera with significant anti-MPP11 antibody titers were subsequently included in an epitope mapping assay to confirm epitope specificity. A series of 84 synthetic peptides (MPP111–84) with a length of 17–19 amino acids overlapping the entire amino acid sequence of MPP11 were used in an IgG ELISA. Interestingly, the vast majority of patient samples recognized peptides derived from the Myb-like domain of the MPP11 protein (fig. 3a). To validate the specificity of the detected anti-MPP11 antibodies, immunoblot assays were performed demonstrating that MPP11-reactive sera specifically recognized MPP11 protein but did not bind to HIVp24 protein (fig. 3b). In addition, reactivity to MPP11 of respective patient sera was specifically inhibited by addition of the MPP11 protein in a dose-dependent manner (fig. 3c).In summary, our data show a strong expression of MPP11 in all AML blasts tested. And more important, the majority of AML patients elicited a humoral immune response against the tumor antigen MPP11. These findings document MPP11 as a highly immunogenic molecule and can be considered as a target structure for developing immunotherapeutic strategies against AML. As a next step in this direction, peptide epitopes recognized by cytotoxic T lymphocytes were already identified [8,9]." @default.
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• W1966107562 date "2012-01-01" @default.
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• W1966107562 title "M-Phase Phosphoprotein 11 Is a Highly Immunogenic Tumor Antigen in Patients with Acute Myeloid Leukemia" @default.
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• W1966107562 doi "https://doi.org/10.1159/000335133" @default.
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