c‐myc‐induced natural killer cell sensitivity of human melanoma cells is reversed by HLA‐B27 transfection

Peltenburg, L. T. C.; Steegenga, Wilma T.; Krüse, K. M.; Schrier, Peter I.

doi:10.1002/eji.1830221040

Cited by 17 publications

(14 citation statements)

References 19 publications

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“…We have previously shown that in human melanoma cells the expression of c-myc is often augmented, leading to downmodulation of the HLA-B expression (Versteeg et al 1988;Versteeg et al 1989 a) as well as elevation of the NK sensitivity of the tumor cells (Versteeg et al 1989b;Peltenburg et al 1992). The downmodulation of HLA-B expression was demonstrated to occur at the level of transcriptional initiation and was, surprisingly, not mediated by the activity of the main MHC class I enhancer, enhancer A ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements

Peltenburg

Schrier

1994

Immunogenetics

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In melanoma, HLA class I expression is suppressed by overexpression of the c-myc oncogene. This suppression has severe consequences for the recognition of these tumor cells by the immune system of the organism. We show here that transcription of the HLA-B locus, which is mainly affected by c-Myc, is downmodulated at the level of initiation of transcription. The transcriptional activity of various HLA-B reporter constructs was tested in a melanoma cell line with low endogenous c-myc expression and in transfectants with high stable and transient c-myc expression. We demonstrated that the responsive region can be mapped to the core promoter region of HLA class I, ruling out any effects of c-myc overexpression on the enhancer A or enhancer B regions. The region subject to downregulation is confined to a 43 base pair fragment encompassing the CCAAT and TATA elements. By coupling this region to a heterologous viral enhancer, we showed that the downmodulation by c-Myc is independent of the presence and nature of an enhancer. These results suggest a mechanism in which c-Myc downregulates the expression of HLA class I genes by interfering with the basal level of transcription.

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Section: Discussionmentioning

confidence: 99%

Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements

Peltenburg

Schrier

1994

Immunogenetics

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“…It has been shown that this susceptibility is determined by the level of HLA-B expression and not by c- myc expression [16]. In human melanoma, c- myc overexpression downmodulates HLA class I surface molecules including HLA-B [17], known to present peptides that are crucial for recognition of foreign proteins by the immune system.…”

Section: Discussionmentioning

confidence: 99%

c<i>-myc</i> Is Not Useful as Prognostic Immunohistochemical Marker in Cutaneous Melanoma

Böni

Bantschapp²,

Müller³

et al. 1998

Dermatology

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Background: Several studies indicate that immunohistochemical detection of the c-myc oncogene might serve as an additional prognostic marker in malignant melanoma. Objective: To study c-myc expression in paraffin-embedded cutaneous melanoma and to correlate to metastatic potential and onset of metastases. Methods: Cytoplasmic c-myc protein expression was visualized using the APAPP method, and reactivity (percent total tumor cells stained) was assessed in 62 formalin-fixed paraffin-embedded primary cutaneous melanomas (21 not metastasizing, mean Breslow 3.0 ± 2.9 mm, 41 metastasizing, mean Breslow 3.1 ± 3.0 mm) and 24 metastases of the same patients. Results: There was no significant difference of c-myc reactivity in cutaneous melanoma who did not metastasize (n = 21, c-myc reactivity 32.7 ± 19.3%, follow-up 10.6 ± 1.8 years) and primaries who metastasized (n = 41, c-myc reactivity 27.7 ± 22.4%, p = 0.29). This finding was independent of the thickness of the primary and was found within thin cutaneous melanoma with a Breslow <0.75 mm (range 0.24–0.65 mm, n = 20, c-myc reactivity 29.1 ± 15.7%, p = 0.32) or within thick cutaneous melanoma with a Breslow >1.5 mm (range 1.6–11 mm, n = 41, c-myc reactivity 29.6 ± 23.8%, p = 0.46). No correlation of c-myc expression between thin cutaneous melanoma, thick cutaneous melanoma (p = 0.83) or metastasizing primaries and their metastases (n = 24, c-myc reactivity 29.3 ± 22%) was found (p = 0.64). The time period until development of first metastasis did not correlate with the percentage of cells expressing c-myc in the primary (p = 0.56). Conclusion: c-myc expression is independent of metastatic potential and onset of metastases and, therefore, does not serve as a prognostic immunohistochemical marker in primary cutaneous melanoma.

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“…This e ect may be mediated by several mechanisms. In melanoma cell lines c-Myc overexpression downregulates MHC class I expression and sensitizes the cells to NK cytolysis (Peltenburg et al, 1992;Versteeg et al, 1989). The sensitization can be reversed by reintroduction of MHC class I molecules by transfection.…”

Section: Introductionmentioning

confidence: 99%

c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

et al. 1999

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The contact of natural killer (NK) cells with foreign cells and with certain virus-infected or tumor cells triggers the cytolytic machinery of NK cells. This triggering leads to exocytosis of the cytotoxic NK cell granules. The oncoproteins c-Myc and E1A render cells vulnerable to NK cell mediated cytolysis yet the mechanisms of sensitization are not well understood. In a model where foreign cells (rat ®broblasts) were cocultured with human IL-2 activated NK cells, we observed that NK cells were capable of e ciently killing their targets only if the cells overexpressed the oncogene c-Myc or E1A. Both the parental and the oncogene expressing ®broblasts similarly triggered phosphoinositide hydrolysis in the bound NK cells, demonstrating that NK cells were cytolytically activated in contact with both resistant parental and oncogene expressing sensitive target ®broblasts. The cell death was independent of wild-type p53 and was not inhibited by an anti-apoptotic protein E1B19K. These results provided evidence that c-Myc and E1A activated the NK cell induced cytolysis at a post-triggering stage of NK cell-target cell interaction. In consistence, the c-Myc and E1A overexpressing ®broblasts were more sensitive to the cytolytic e ects of isolated NK cellderived granules than parental cells. The data indicate that oncogenes activate the cytotoxicity of NK cell granules. This mechanism can have a role in directing the cytolytic action of NK cells towards the virus-infected and cancer cells.

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c‐myc‐induced natural killer cell sensitivity of human melanoma cells is reversed by HLA‐B27 transfection

Cited by 17 publications

References 19 publications

Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements

Transcriptional suppression of HLA-B expression by c-Myc is mediated through the core promoter elements

c<i>-myc</i> Is Not Useful as Prognostic Immunohistochemical Marker in Cutaneous Melanoma

c-Myc and E1A induced cellular sensitivity to activated NK cells involves cytotoxic granules as death effectors

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