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KSHV Latency Locus Cooperates with Myc to Drive Lymphoma in Mice.

Sin SH, Kim Y, Eason A, Dittmer DP - PLoS Pathog. (2015)

Bottom Line: Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma and B-cell malignancies.Mechanisms of KSHV-induced oncogenesis remain elusive, however, in part due to lack of reliable in vivo models.These data indicate that the KSHV latency locus cooperates with the deregulated Myc pathways to further lymphoma progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Program in Global Oncology, Lineberger Comprehensive Cancer Center, and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma and B-cell malignancies. Mechanisms of KSHV-induced oncogenesis remain elusive, however, in part due to lack of reliable in vivo models. Recently, we showed that transgenic mice expressing the KSHV latent genes, including all viral microRNAs, developed splenic B cell hyperplasia with 100% penetrance, but only a fraction converted to B cell lymphomas, suggesting that cooperative oncogenic events were missing. Myc was chosen as a possible candidate, because Myc is deregulated in many B cell lymphomas. We crossed KSHV latency locus transgenic (latency) mice to Cα Myc transgenic (Myc) mice. By itself these Myc transgenic mice develop lymphomas only rarely. In the double transgenic mice (Myc/latency) we observed plasmacytosis, severe extramedullary hematopoiesis in spleen and liver, and increased proliferation of splenocytes. Myc/latency mice developed frank lymphoma at a higher rate than single transgenic latency or Myc mice. These data indicate that the KSHV latency locus cooperates with the deregulated Myc pathways to further lymphoma progression.

No MeSH data available.


Related in: MedlinePlus

Augmented tumorigenicity by cooperation of KSHV latency locus and Myc.(A-B) Survival plot of the wild-type (C57BL/6) and latency, and the Myc and Myc/latency mouse cohorts. (C) Splenomegaly was observed in the Myc/latency mice. (D-E) Spleen section was shown and mitotic figures (black arrows) were found in the Myc/latency mouse. H&E staining. (F-G) Normal splenic architecture was presented in the Myc mouse. H&E staining. Representative images are shown. (H) Mitotic figures were counted for 5 high power field images (400X) per sample (42 for Myc and 40 for Myc/latency mice). ** represents significant difference with p ≤ 0.005 by ANOVA.
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ppat.1005135.g004: Augmented tumorigenicity by cooperation of KSHV latency locus and Myc.(A-B) Survival plot of the wild-type (C57BL/6) and latency, and the Myc and Myc/latency mouse cohorts. (C) Splenomegaly was observed in the Myc/latency mice. (D-E) Spleen section was shown and mitotic figures (black arrows) were found in the Myc/latency mouse. H&E staining. (F-G) Normal splenic architecture was presented in the Myc mouse. H&E staining. Representative images are shown. (H) Mitotic figures were counted for 5 high power field images (400X) per sample (42 for Myc and 40 for Myc/latency mice). ** represents significant difference with p ≤ 0.005 by ANOVA.

Mentions: To formally test the hypothesis that Myc and KSHV latent genes cooperate to induce lymphoid hyperplasia and neoplasia, Myc transgenic (n = 42), the KSHV latency locus transgenic (n = 41), and Myc/KSHV latency locus double transgenic mice (n = 40) were monitored for 500 days (Fig 4A and 4B). Wild-type B6 mice were tumor-free for 500 days. Single transgenic Myc mice remained tumor-free until 200 days, while both latency and Myc/latency mice started to develop tumors around 130 days. The overall survival rate was significantly lower in the Myc/latency mice, when compared to that of Myc mice (p ≤ 0.021 by log-rank test) (Fig 4B). Given the weak tumor phenotypes of these particular Myc transgenic mice [7], we surmise that the increased rate of tumor incidence is attributable to cooperation of KSHV latent genes and Myc.


KSHV Latency Locus Cooperates with Myc to Drive Lymphoma in Mice.

Sin SH, Kim Y, Eason A, Dittmer DP - PLoS Pathog. (2015)

Augmented tumorigenicity by cooperation of KSHV latency locus and Myc.(A-B) Survival plot of the wild-type (C57BL/6) and latency, and the Myc and Myc/latency mouse cohorts. (C) Splenomegaly was observed in the Myc/latency mice. (D-E) Spleen section was shown and mitotic figures (black arrows) were found in the Myc/latency mouse. H&E staining. (F-G) Normal splenic architecture was presented in the Myc mouse. H&E staining. Representative images are shown. (H) Mitotic figures were counted for 5 high power field images (400X) per sample (42 for Myc and 40 for Myc/latency mice). ** represents significant difference with p ≤ 0.005 by ANOVA.
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Related In: Results  -  Collection

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ppat.1005135.g004: Augmented tumorigenicity by cooperation of KSHV latency locus and Myc.(A-B) Survival plot of the wild-type (C57BL/6) and latency, and the Myc and Myc/latency mouse cohorts. (C) Splenomegaly was observed in the Myc/latency mice. (D-E) Spleen section was shown and mitotic figures (black arrows) were found in the Myc/latency mouse. H&E staining. (F-G) Normal splenic architecture was presented in the Myc mouse. H&E staining. Representative images are shown. (H) Mitotic figures were counted for 5 high power field images (400X) per sample (42 for Myc and 40 for Myc/latency mice). ** represents significant difference with p ≤ 0.005 by ANOVA.
Mentions: To formally test the hypothesis that Myc and KSHV latent genes cooperate to induce lymphoid hyperplasia and neoplasia, Myc transgenic (n = 42), the KSHV latency locus transgenic (n = 41), and Myc/KSHV latency locus double transgenic mice (n = 40) were monitored for 500 days (Fig 4A and 4B). Wild-type B6 mice were tumor-free for 500 days. Single transgenic Myc mice remained tumor-free until 200 days, while both latency and Myc/latency mice started to develop tumors around 130 days. The overall survival rate was significantly lower in the Myc/latency mice, when compared to that of Myc mice (p ≤ 0.021 by log-rank test) (Fig 4B). Given the weak tumor phenotypes of these particular Myc transgenic mice [7], we surmise that the increased rate of tumor incidence is attributable to cooperation of KSHV latent genes and Myc.

Bottom Line: Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma and B-cell malignancies.Mechanisms of KSHV-induced oncogenesis remain elusive, however, in part due to lack of reliable in vivo models.These data indicate that the KSHV latency locus cooperates with the deregulated Myc pathways to further lymphoma progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Program in Global Oncology, Lineberger Comprehensive Cancer Center, and Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT
Kaposi sarcoma-associated herpesvirus (KSHV) has been linked to Kaposi sarcoma and B-cell malignancies. Mechanisms of KSHV-induced oncogenesis remain elusive, however, in part due to lack of reliable in vivo models. Recently, we showed that transgenic mice expressing the KSHV latent genes, including all viral microRNAs, developed splenic B cell hyperplasia with 100% penetrance, but only a fraction converted to B cell lymphomas, suggesting that cooperative oncogenic events were missing. Myc was chosen as a possible candidate, because Myc is deregulated in many B cell lymphomas. We crossed KSHV latency locus transgenic (latency) mice to Cα Myc transgenic (Myc) mice. By itself these Myc transgenic mice develop lymphomas only rarely. In the double transgenic mice (Myc/latency) we observed plasmacytosis, severe extramedullary hematopoiesis in spleen and liver, and increased proliferation of splenocytes. Myc/latency mice developed frank lymphoma at a higher rate than single transgenic latency or Myc mice. These data indicate that the KSHV latency locus cooperates with the deregulated Myc pathways to further lymphoma progression.

No MeSH data available.


Related in: MedlinePlus