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NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas.

Reed SM, Hagen J, Muniz VP, Rosean TR, Borcherding N, Sciegienka S, Goeken JA, Naumann PW, Zhang W, Tompkins VS, Janz S, Meyerholz DK, Quelle DE - PLoS ONE (2014)

Bottom Line: It is a novel activator of the ARF-Mdm2-Tip60-p53 tumor suppressor pathway as well as other undefined pathways important for genome maintenance.Unexpectedly, basal p53 expression and activity was largely unaffected by NIAM loss in isolated splenic B cells.In sum, NIAM down-regulation in vivo results in a significant predisposition to developing benign tumors or early stage cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America; Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
Nuclear Interactor of ARF and Mdm2 (NIAM, gene designation Tbrg1) is a largely unstudied inhibitor of cell proliferation that helps maintain chromosomal stability. It is a novel activator of the ARF-Mdm2-Tip60-p53 tumor suppressor pathway as well as other undefined pathways important for genome maintenance. To examine its predicted role as a tumor suppressor, we generated NIAM mutant (NIAM(m/m)) mice homozygous for a β-galactosidase expressing gene-trap cassette in the endogenous gene. The mutant mice expressed significantly lower levels of NIAM protein in tissues compared to wild-type animals. Fifty percent of aged NIAM deficient mice (14 to 21 months) developed proliferative lesions, including a uterine hemangioma, pulmonary papillary adenoma, and a Harderian gland adenoma. No age-matched wild-type or NIAM(+/m) heterozygous animals developed lesions. In the spleen, NIAM(m/m) mice had prominent white pulp expansion which correlated with enhanced increased reactive lymphoid hyperplasia and evidence of systemic inflammation. Notably, 17% of NIAM mutant mice had splenic white pulp features indicating early B-cell lymphoma. This correlated with selective expansion of marginal zone B cells in the spleens of younger, tumor-free NIAM-deficient mice. Unexpectedly, basal p53 expression and activity was largely unaffected by NIAM loss in isolated splenic B cells. In sum, NIAM down-regulation in vivo results in a significant predisposition to developing benign tumors or early stage cancers. These mice represent an outstanding platform for dissecting NIAM's role in tumorigenesis and various anti-cancer pathways, including p53 signaling.

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Marginal zone B cells are increased in NIAMm/m mice.Flow cytometric analyses of splenic B cell development. Splenic B cells were isolated from young, 6 month old tumor-free wild-type (+/+) and NIAM mutant (m/m) mice (three of each genotype). A. Representative flow cytometry plots of NIAM wild-type versus m/m IgM positive splenocytes. Transitional (CD21lo/CD23-), follicular (CD21+/CD23+) and marginal zone (CD21hi/CD23-) B cells are identified. B. Average frequency of follicular (top left), transitional (top right), and marginal zone (bottom left) B cells from mice of the indicated genotypes. Average marginal zone B cell numbers are also shown (bottom right). All p values were calculated using unpaired, two-tailed Student's T tests.
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pone-0112126-g006: Marginal zone B cells are increased in NIAMm/m mice.Flow cytometric analyses of splenic B cell development. Splenic B cells were isolated from young, 6 month old tumor-free wild-type (+/+) and NIAM mutant (m/m) mice (three of each genotype). A. Representative flow cytometry plots of NIAM wild-type versus m/m IgM positive splenocytes. Transitional (CD21lo/CD23-), follicular (CD21+/CD23+) and marginal zone (CD21hi/CD23-) B cells are identified. B. Average frequency of follicular (top left), transitional (top right), and marginal zone (bottom left) B cells from mice of the indicated genotypes. Average marginal zone B cell numbers are also shown (bottom right). All p values were calculated using unpaired, two-tailed Student's T tests.

Mentions: Since aged NIAMm/m mice have enlarged spleens and some develop B-cell lymphoma, we evaluated B cell development in younger, tumor-free mice (6 months of age, 3 of each NIAM genotype) to identify potential pre-malignant changes that could give rise to B-cell tumors. Analysis of B cell development in the bone marrow of NIAMm/m mice revealed no alterations compared to wild-type control animals (Fig. S1). Specifically, there were no significant differences in the frequency of pro/pre (B220+IgM-, p = 0.4783), immature (B220+IgM+, p = 0.7693) or mature (B220hiIgM+, p = 0.8048) B cells. Analysis of B cells from the spleen likewise showed no difference in the frequency of transitional (CD21lo/CD23-) or follicular (CD21+/CD23+) B cells (Fig. 6A, B; p values of 0.5068 and 0.9325, respectively). In contrast, splenic marginal zone B cells (CD21hi/CD23-) were significantly increased in frequency (p = 0.0281) and number (p = 0.0144) in NIAMm/m mice compared to wild-type controls (Fig. 6). These results uncover a specific sensitivity of splenic marginal zone B cells to NIAM loss, which may suggest that NIAM normally restricts their proliferation.


NIAM-deficient mice are predisposed to the development of proliferative lesions including B-cell lymphomas.

Reed SM, Hagen J, Muniz VP, Rosean TR, Borcherding N, Sciegienka S, Goeken JA, Naumann PW, Zhang W, Tompkins VS, Janz S, Meyerholz DK, Quelle DE - PLoS ONE (2014)

Marginal zone B cells are increased in NIAMm/m mice.Flow cytometric analyses of splenic B cell development. Splenic B cells were isolated from young, 6 month old tumor-free wild-type (+/+) and NIAM mutant (m/m) mice (three of each genotype). A. Representative flow cytometry plots of NIAM wild-type versus m/m IgM positive splenocytes. Transitional (CD21lo/CD23-), follicular (CD21+/CD23+) and marginal zone (CD21hi/CD23-) B cells are identified. B. Average frequency of follicular (top left), transitional (top right), and marginal zone (bottom left) B cells from mice of the indicated genotypes. Average marginal zone B cell numbers are also shown (bottom right). All p values were calculated using unpaired, two-tailed Student's T tests.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4231569&req=5

pone-0112126-g006: Marginal zone B cells are increased in NIAMm/m mice.Flow cytometric analyses of splenic B cell development. Splenic B cells were isolated from young, 6 month old tumor-free wild-type (+/+) and NIAM mutant (m/m) mice (three of each genotype). A. Representative flow cytometry plots of NIAM wild-type versus m/m IgM positive splenocytes. Transitional (CD21lo/CD23-), follicular (CD21+/CD23+) and marginal zone (CD21hi/CD23-) B cells are identified. B. Average frequency of follicular (top left), transitional (top right), and marginal zone (bottom left) B cells from mice of the indicated genotypes. Average marginal zone B cell numbers are also shown (bottom right). All p values were calculated using unpaired, two-tailed Student's T tests.
Mentions: Since aged NIAMm/m mice have enlarged spleens and some develop B-cell lymphoma, we evaluated B cell development in younger, tumor-free mice (6 months of age, 3 of each NIAM genotype) to identify potential pre-malignant changes that could give rise to B-cell tumors. Analysis of B cell development in the bone marrow of NIAMm/m mice revealed no alterations compared to wild-type control animals (Fig. S1). Specifically, there were no significant differences in the frequency of pro/pre (B220+IgM-, p = 0.4783), immature (B220+IgM+, p = 0.7693) or mature (B220hiIgM+, p = 0.8048) B cells. Analysis of B cells from the spleen likewise showed no difference in the frequency of transitional (CD21lo/CD23-) or follicular (CD21+/CD23+) B cells (Fig. 6A, B; p values of 0.5068 and 0.9325, respectively). In contrast, splenic marginal zone B cells (CD21hi/CD23-) were significantly increased in frequency (p = 0.0281) and number (p = 0.0144) in NIAMm/m mice compared to wild-type controls (Fig. 6). These results uncover a specific sensitivity of splenic marginal zone B cells to NIAM loss, which may suggest that NIAM normally restricts their proliferation.

Bottom Line: It is a novel activator of the ARF-Mdm2-Tip60-p53 tumor suppressor pathway as well as other undefined pathways important for genome maintenance.Unexpectedly, basal p53 expression and activity was largely unaffected by NIAM loss in isolated splenic B cells.In sum, NIAM down-regulation in vivo results in a significant predisposition to developing benign tumors or early stage cancers.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America; Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
Nuclear Interactor of ARF and Mdm2 (NIAM, gene designation Tbrg1) is a largely unstudied inhibitor of cell proliferation that helps maintain chromosomal stability. It is a novel activator of the ARF-Mdm2-Tip60-p53 tumor suppressor pathway as well as other undefined pathways important for genome maintenance. To examine its predicted role as a tumor suppressor, we generated NIAM mutant (NIAM(m/m)) mice homozygous for a β-galactosidase expressing gene-trap cassette in the endogenous gene. The mutant mice expressed significantly lower levels of NIAM protein in tissues compared to wild-type animals. Fifty percent of aged NIAM deficient mice (14 to 21 months) developed proliferative lesions, including a uterine hemangioma, pulmonary papillary adenoma, and a Harderian gland adenoma. No age-matched wild-type or NIAM(+/m) heterozygous animals developed lesions. In the spleen, NIAM(m/m) mice had prominent white pulp expansion which correlated with enhanced increased reactive lymphoid hyperplasia and evidence of systemic inflammation. Notably, 17% of NIAM mutant mice had splenic white pulp features indicating early B-cell lymphoma. This correlated with selective expansion of marginal zone B cells in the spleens of younger, tumor-free NIAM-deficient mice. Unexpectedly, basal p53 expression and activity was largely unaffected by NIAM loss in isolated splenic B cells. In sum, NIAM down-regulation in vivo results in a significant predisposition to developing benign tumors or early stage cancers. These mice represent an outstanding platform for dissecting NIAM's role in tumorigenesis and various anti-cancer pathways, including p53 signaling.

Show MeSH
Related in: MedlinePlus