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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

Severe EMH in the Myc/latency mice.(A-B) Severe EMH was found in spleen in the Myc/latency mice. Black arrow represents megakaryocyte. H&E staining. (C-D) Liver from the Myc/latency mice showed severe EMH. Yellow arrow indicates cluster of erythroid precursors in portal vein. H&E staining. (E-F) Decreased hematopoiesis was found in femoral BM from the Myc/latency mice. Black asterisk represents megakaryocyte. (G) The number of megakaryocytes was counted in 5 high field images (400X) per femoral BM section from 6 mice per each genotype and plotted. H&E staining. Representative images are shown.
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ppat.1005135.g005: Severe EMH in the Myc/latency mice.(A-B) Severe EMH was found in spleen in the Myc/latency mice. Black arrow represents megakaryocyte. H&E staining. (C-D) Liver from the Myc/latency mice showed severe EMH. Yellow arrow indicates cluster of erythroid precursors in portal vein. H&E staining. (E-F) Decreased hematopoiesis was found in femoral BM from the Myc/latency mice. Black asterisk represents megakaryocyte. (G) The number of megakaryocytes was counted in 5 high field images (400X) per femoral BM section from 6 mice per each genotype and plotted. H&E staining. Representative images are shown.

Mentions: Lymphoma observed in the Myc/latency mouse cohort is summarized in Table 2. Mice with early lymphoma or lymphocytic lymphoma exhibited disrupted splenic architecture and white pulp expanded by large lymphocytes with frequent mitotic figures, whereas mice diagnosed as normal had regular splenic architectures with clearly defined GCs. Mice with lymphoma also displayed severe extramedullary hematopoiesis, showing augmented frequency of megakaryocytes in spleen (Fig 5A and 5B) and elevated numbers of erythroid precursors in portal area of liver (Fig 5C and 5D). BM was examined to see if a failure in hematopoiesis from the Myc/latency mice may induce severe extramedullary hematopoiesis (EMH) in the spleen and liver for compensation (Fig 5E and 5F). Frequencies of myeloid and erythroid precursors were not significantly different between the Myc and the Myc/latency mice. However, the number of megakaryocytes was decreased in the Myc/latency mice (Fig 5G; p ≤ 0.017 by ANOVA), suggesting that inadequate hematopoiesis in BM from the Myc/latency mouse drives severe EMH in the spleen and liver. Mice diagnosed with lymphoid hyperplasia retained normal splenic follicular architecture, but lacked discernible GCs with pale MZ (Table 2; mouse #176). In sum, even the weak Cα Myc allele can cooperate with the KSHV latent locus to foster lymphoma development in vivo.


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

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

Severe EMH in the Myc/latency mice.(A-B) Severe EMH was found in spleen in the Myc/latency mice. Black arrow represents megakaryocyte. H&E staining. (C-D) Liver from the Myc/latency mice showed severe EMH. Yellow arrow indicates cluster of erythroid precursors in portal vein. H&E staining. (E-F) Decreased hematopoiesis was found in femoral BM from the Myc/latency mice. Black asterisk represents megakaryocyte. (G) The number of megakaryocytes was counted in 5 high field images (400X) per femoral BM section from 6 mice per each genotype and plotted. H&E staining. Representative images are shown.
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ppat.1005135.g005: Severe EMH in the Myc/latency mice.(A-B) Severe EMH was found in spleen in the Myc/latency mice. Black arrow represents megakaryocyte. H&E staining. (C-D) Liver from the Myc/latency mice showed severe EMH. Yellow arrow indicates cluster of erythroid precursors in portal vein. H&E staining. (E-F) Decreased hematopoiesis was found in femoral BM from the Myc/latency mice. Black asterisk represents megakaryocyte. (G) The number of megakaryocytes was counted in 5 high field images (400X) per femoral BM section from 6 mice per each genotype and plotted. H&E staining. Representative images are shown.
Mentions: Lymphoma observed in the Myc/latency mouse cohort is summarized in Table 2. Mice with early lymphoma or lymphocytic lymphoma exhibited disrupted splenic architecture and white pulp expanded by large lymphocytes with frequent mitotic figures, whereas mice diagnosed as normal had regular splenic architectures with clearly defined GCs. Mice with lymphoma also displayed severe extramedullary hematopoiesis, showing augmented frequency of megakaryocytes in spleen (Fig 5A and 5B) and elevated numbers of erythroid precursors in portal area of liver (Fig 5C and 5D). BM was examined to see if a failure in hematopoiesis from the Myc/latency mice may induce severe extramedullary hematopoiesis (EMH) in the spleen and liver for compensation (Fig 5E and 5F). Frequencies of myeloid and erythroid precursors were not significantly different between the Myc and the Myc/latency mice. However, the number of megakaryocytes was decreased in the Myc/latency mice (Fig 5G; p ≤ 0.017 by ANOVA), suggesting that inadequate hematopoiesis in BM from the Myc/latency mouse drives severe EMH in the spleen and liver. Mice diagnosed with lymphoid hyperplasia retained normal splenic follicular architecture, but lacked discernible GCs with pale MZ (Table 2; mouse #176). In sum, even the weak Cα Myc allele can cooperate with the KSHV latent locus to foster lymphoma development in vivo.

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