Limits...
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: NFKB2 suppression by Myc was also confirmed in primary human BL.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.

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

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
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.


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: NFKB2 suppression by Myc was also confirmed in primary human BL.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.

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