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Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells.

Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA - J. Exp. Med. (2001)

Bottom Line: Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis.Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms.These data provide novel evidence that leukemia, like certain other cancers, can arise as the result of chronic stimulation by a proinflammatory cytokine.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.

ABSTRACT
Inflammation likely has a role in the early genesis of certain malignancies. Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis. Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms. Here, we engineered a transgenic mouse to overexpress IL-15 by eliminating these posttranscriptional checkpoints. IL-15 transgenic mice have early expansions in natural killer (NK) and CD8+ T lymphocytes. Later, these mice develop fatal lymphocytic leukemia with a T-NK phenotype. These data provide novel evidence that leukemia, like certain other cancers, can arise as the result of chronic stimulation by a proinflammatory cytokine.

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Multiorgan lymphocytic infiltration in IL-15tg mice. Histology sections of skin (a–c), lung (d–f), and liver (g–i) stained with hematoxylin and eosin. Low power (10×) micrographs contrast wild-type (a, d, and g) and IL-15tg (b, e, and h) tissues. High power (40×) micrographs demonstrate the lymphocytic morphology of the infiltrating cells in the IL-15tg mice (c, f, and i). See Results for detailed description of the pathology.
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Figure 10: Multiorgan lymphocytic infiltration in IL-15tg mice. Histology sections of skin (a–c), lung (d–f), and liver (g–i) stained with hematoxylin and eosin. Low power (10×) micrographs contrast wild-type (a, d, and g) and IL-15tg (b, e, and h) tissues. High power (40×) micrographs demonstrate the lymphocytic morphology of the infiltrating cells in the IL-15tg mice (c, f, and i). See Results for detailed description of the pathology.

Mentions: Fig. 10 illustrates the skin, lung, and liver pathology found in IL-15tg mice. Skin infiltrates were dense within the dermis with individual lymphoid cells present within the epidermis (Fig. 10b and Fig. c). Also remarkable was the presence of mast cells within the dermal infiltrate. Multiple skin ulcerations were evident, and acute inflammatory cells were present at these foci. In immunohistochemical studies on frozen tissue, the invading lymphocytes were CD3 positive (data not shown), whereas no mouse NK cell marker is available for use on tissue sections. The pattern of cutaneous involvement found in these animals is very similar to that seen in patients with NK/T cell lymphomas 40. Other skin changes consistent with long-term inflammation include epidermal hyperplasia, hyperkeratosis, and loss of adnexal structures (e.g., hair follicles).


Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells.

Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA - J. Exp. Med. (2001)

Multiorgan lymphocytic infiltration in IL-15tg mice. Histology sections of skin (a–c), lung (d–f), and liver (g–i) stained with hematoxylin and eosin. Low power (10×) micrographs contrast wild-type (a, d, and g) and IL-15tg (b, e, and h) tissues. High power (40×) micrographs demonstrate the lymphocytic morphology of the infiltrating cells in the IL-15tg mice (c, f, and i). See Results for detailed description of the pathology.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193336&req=5

Figure 10: Multiorgan lymphocytic infiltration in IL-15tg mice. Histology sections of skin (a–c), lung (d–f), and liver (g–i) stained with hematoxylin and eosin. Low power (10×) micrographs contrast wild-type (a, d, and g) and IL-15tg (b, e, and h) tissues. High power (40×) micrographs demonstrate the lymphocytic morphology of the infiltrating cells in the IL-15tg mice (c, f, and i). See Results for detailed description of the pathology.
Mentions: Fig. 10 illustrates the skin, lung, and liver pathology found in IL-15tg mice. Skin infiltrates were dense within the dermis with individual lymphoid cells present within the epidermis (Fig. 10b and Fig. c). Also remarkable was the presence of mast cells within the dermal infiltrate. Multiple skin ulcerations were evident, and acute inflammatory cells were present at these foci. In immunohistochemical studies on frozen tissue, the invading lymphocytes were CD3 positive (data not shown), whereas no mouse NK cell marker is available for use on tissue sections. The pattern of cutaneous involvement found in these animals is very similar to that seen in patients with NK/T cell lymphomas 40. Other skin changes consistent with long-term inflammation include epidermal hyperplasia, hyperkeratosis, and loss of adnexal structures (e.g., hair follicles).

Bottom Line: Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis.Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms.These data provide novel evidence that leukemia, like certain other cancers, can arise as the result of chronic stimulation by a proinflammatory cytokine.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, The Ohio State University, Columbus, Ohio 43210, USA.

ABSTRACT
Inflammation likely has a role in the early genesis of certain malignancies. Interleukin (IL)-15, a proinflammatory cytokine and growth factor, is required for lymphocyte homeostasis. Intriguingly, the expression of IL-15 protein is tightly controlled by multiple posttranscriptional mechanisms. Here, we engineered a transgenic mouse to overexpress IL-15 by eliminating these posttranscriptional checkpoints. IL-15 transgenic mice have early expansions in natural killer (NK) and CD8+ T lymphocytes. Later, these mice develop fatal lymphocytic leukemia with a T-NK phenotype. These data provide novel evidence that leukemia, like certain other cancers, can arise as the result of chronic stimulation by a proinflammatory cytokine.

Show MeSH
Related in: MedlinePlus