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Myc suppression of Nfkb2 accelerates lymphomagenesis.

Keller U, Huber J, Nilsson JA, Fallahi M, Hall MA, Peschel C, Cleveland JL - BMC Cancer (2010)

Bottom Line: Myc overexpression is associated with reduced activity of Rel/NF-kappaB, transcription factors that control the immune response, cell survival, and transformation, and that are frequently altered in cancer.NFKB2 suppression by Myc was also confirmed in primary human BL.These data thus link Myc-driven lymphomagenesis to the non-canonical NF-kappaB pathway.

View Article: PubMed Central - HTML - PubMed

Affiliation: III. Medical Department, Technische Universität München, Munich, Germany. ulrich.keller@lrz.tum.de

ABSTRACT

Background: Deregulated c-Myc expression is a hallmark of several human cancers where it promotes proliferation and an aggressive tumour phenotype. Myc overexpression is associated with reduced activity of Rel/NF-kappaB, transcription factors that control the immune response, cell survival, and transformation, and that are frequently altered in cancer. The Rel/NF-kappaB family member NFKB2 is altered by chromosomal translocations or deletions in lymphoid malignancies and deletion of the C-terminal ankyrin domain of NF-kappaB2 augments lymphocyte proliferation.

Methods: Precancerous Emicro-Myc-transgenic B cells, Emicro-Myc lymphomas and human Burkitt lymphoma samples were assessed for Nfkb2 expression. The contribution of Nfkb2 to Myc-driven apoptosis, proliferation, and lymphomagenesis was tested genetically in vivo.

Results: Here we report that the Myc oncoprotein suppresses Nfkb2 expression in vitro in primary mouse fibroblasts and B cells, and in vivo in the Emicro-Myc transgenic mouse model of human Burkitt lymphoma (BL). NFKB2 suppression by Myc was also confirmed in primary human BL. Promoter-reporter assays indicate that Myc-mediated suppression of Nfkb2 occurs at the level of transcription. The contribution of Nfkb2 to Myc-driven lymphomagenesis was tested in vivo, where Nfkb2 loss was shown to accelerate lymphoma development in Emicro-Myc transgenic mice, by impairing Myc's apoptotic response.

Conclusions: Nfkb2 is suppressed by c-Myc and harnesses Myc-driven lymphomagenesis. These data thus link Myc-driven lymphomagenesis to the non-canonical NF-kappaB pathway.

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Myc targets the Rel/NF-κB network in precancerous B cells and lymphomas. Hierarchical clustering of Rel/Nfkb family members, upstream kinases that regulate the NF-κB pathway, and selected control genes was performed using RNA prepared from B220+ splenic B cells from five weanling-age wild type mice (wt), from five Eμ-Myc transgenic mice (Eμ-Myc), and from thirteen Eμ-Myc lymphomas. Probe set signals were normalized to the mean across wt samples, and values of each individual sample are represented by a colour, with green corresponding to expression below, red corresponding to expression above, and black corresponding to expression equal to the wt mean expression.
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Figure 1: Myc targets the Rel/NF-κB network in precancerous B cells and lymphomas. Hierarchical clustering of Rel/Nfkb family members, upstream kinases that regulate the NF-κB pathway, and selected control genes was performed using RNA prepared from B220+ splenic B cells from five weanling-age wild type mice (wt), from five Eμ-Myc transgenic mice (Eμ-Myc), and from thirteen Eμ-Myc lymphomas. Probe set signals were normalized to the mean across wt samples, and values of each individual sample are represented by a colour, with green corresponding to expression below, red corresponding to expression above, and black corresponding to expression equal to the wt mean expression.

Mentions: In the Eμ-Myc model of human B cell lymphoma disease progression is characterized by a pre-neoplastic state in which high proliferative rates of Eμ-Myc B cells are offset by high levels of apoptosis, which is then disabled during progression to the malignant state [24,27]. The Rel/NF-κB pathway is suppressed in Myc-transgenic precancerous B cells [22] and in human B lymphoma [21], yet the underlying targets in this response are not resolved. To address this issue we initially assessed the expression of NF-κB components in B220+ splenic B cells of 4 week-old precancerous Eμ-Myc transgenic mice (n = 5) and their wild type littermate controls (n = 5), and in several (n = 13) Eμ-Myc lymphomas. As expected, there were clear increases in the levels of the established Myc targets Cad [28] and Rcl [29], in precancerous Eμ-Myc B cells, and even more so in Eμ-Myc lymphomas, compared to their levels in wild type splenic B cells (Figure 1, lower panel). In contrast, there were reduced levels of nearly all mRNAs encoding Rel/Nfkb factors, their inhibitors (Nfkbia and Nfkbib), and their upstream regulators in pre-malignant Eμ-Myc B cells compared to their levels expressed in wild type B cells (Figure 1). Strikingly, this response was significantly augmented in frank Eμ-Myc lymphomas (Figure 1). Thus, Myc-mediated suppression of the Rel/NF-κB pathway is augmented following the switch to the neoplastic state.


Myc suppression of Nfkb2 accelerates lymphomagenesis.

Keller U, Huber J, Nilsson JA, Fallahi M, Hall MA, Peschel C, Cleveland JL - BMC Cancer (2010)

Myc targets the Rel/NF-κB network in precancerous B cells and lymphomas. Hierarchical clustering of Rel/Nfkb family members, upstream kinases that regulate the NF-κB pathway, and selected control genes was performed using RNA prepared from B220+ splenic B cells from five weanling-age wild type mice (wt), from five Eμ-Myc transgenic mice (Eμ-Myc), and from thirteen Eμ-Myc lymphomas. Probe set signals were normalized to the mean across wt samples, and values of each individual sample are represented by a colour, with green corresponding to expression below, red corresponding to expression above, and black corresponding to expression equal to the wt mean expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2902445&req=5

Figure 1: Myc targets the Rel/NF-κB network in precancerous B cells and lymphomas. Hierarchical clustering of Rel/Nfkb family members, upstream kinases that regulate the NF-κB pathway, and selected control genes was performed using RNA prepared from B220+ splenic B cells from five weanling-age wild type mice (wt), from five Eμ-Myc transgenic mice (Eμ-Myc), and from thirteen Eμ-Myc lymphomas. Probe set signals were normalized to the mean across wt samples, and values of each individual sample are represented by a colour, with green corresponding to expression below, red corresponding to expression above, and black corresponding to expression equal to the wt mean expression.
Mentions: In the Eμ-Myc model of human B cell lymphoma disease progression is characterized by a pre-neoplastic state in which high proliferative rates of Eμ-Myc B cells are offset by high levels of apoptosis, which is then disabled during progression to the malignant state [24,27]. The Rel/NF-κB pathway is suppressed in Myc-transgenic precancerous B cells [22] and in human B lymphoma [21], yet the underlying targets in this response are not resolved. To address this issue we initially assessed the expression of NF-κB components in B220+ splenic B cells of 4 week-old precancerous Eμ-Myc transgenic mice (n = 5) and their wild type littermate controls (n = 5), and in several (n = 13) Eμ-Myc lymphomas. As expected, there were clear increases in the levels of the established Myc targets Cad [28] and Rcl [29], in precancerous Eμ-Myc B cells, and even more so in Eμ-Myc lymphomas, compared to their levels in wild type splenic B cells (Figure 1, lower panel). In contrast, there were reduced levels of nearly all mRNAs encoding Rel/Nfkb factors, their inhibitors (Nfkbia and Nfkbib), and their upstream regulators in pre-malignant Eμ-Myc B cells compared to their levels expressed in wild type B cells (Figure 1). Strikingly, this response was significantly augmented in frank Eμ-Myc lymphomas (Figure 1). Thus, Myc-mediated suppression of the Rel/NF-κB pathway is augmented following the switch to the neoplastic state.

Bottom Line: Myc overexpression is associated with reduced activity of Rel/NF-kappaB, transcription factors that control the immune response, cell survival, and transformation, and that are frequently altered in cancer.NFKB2 suppression by Myc was also confirmed in primary human BL.These data thus link Myc-driven lymphomagenesis to the non-canonical NF-kappaB pathway.

View Article: PubMed Central - HTML - PubMed

Affiliation: III. Medical Department, Technische Universität München, Munich, Germany. ulrich.keller@lrz.tum.de

ABSTRACT

Background: Deregulated c-Myc expression is a hallmark of several human cancers where it promotes proliferation and an aggressive tumour phenotype. Myc overexpression is associated with reduced activity of Rel/NF-kappaB, transcription factors that control the immune response, cell survival, and transformation, and that are frequently altered in cancer. The Rel/NF-kappaB family member NFKB2 is altered by chromosomal translocations or deletions in lymphoid malignancies and deletion of the C-terminal ankyrin domain of NF-kappaB2 augments lymphocyte proliferation.

Methods: Precancerous Emicro-Myc-transgenic B cells, Emicro-Myc lymphomas and human Burkitt lymphoma samples were assessed for Nfkb2 expression. The contribution of Nfkb2 to Myc-driven apoptosis, proliferation, and lymphomagenesis was tested genetically in vivo.

Results: Here we report that the Myc oncoprotein suppresses Nfkb2 expression in vitro in primary mouse fibroblasts and B cells, and in vivo in the Emicro-Myc transgenic mouse model of human Burkitt lymphoma (BL). NFKB2 suppression by Myc was also confirmed in primary human BL. Promoter-reporter assays indicate that Myc-mediated suppression of Nfkb2 occurs at the level of transcription. The contribution of Nfkb2 to Myc-driven lymphomagenesis was tested in vivo, where Nfkb2 loss was shown to accelerate lymphoma development in Emicro-Myc transgenic mice, by impairing Myc's apoptotic response.

Conclusions: Nfkb2 is suppressed by c-Myc and harnesses Myc-driven lymphomagenesis. These data thus link Myc-driven lymphomagenesis to the non-canonical NF-kappaB pathway.

Show MeSH
Related in: MedlinePlus