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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

KSHV latency locus confers hyper-responsiveness to LPS in the environment of forced Myc overexpression.Proliferation was evaluated by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into DNA. Splenic B cells from the transgenic (n = 5) and wild-type mice (n = 5) were cultured with varying doses of LPS (A), or anti-IgM (B), or anti-CD40 antibody (C), or loxoribine (D), or CpG (E), or non-CpG (F) for 72 hours. Relative fluorescence unit (RFU) was measured and is expressed as ex vivo cell proliferation.
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ppat.1005135.g003: KSHV latency locus confers hyper-responsiveness to LPS in the environment of forced Myc overexpression.Proliferation was evaluated by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into DNA. Splenic B cells from the transgenic (n = 5) and wild-type mice (n = 5) were cultured with varying doses of LPS (A), or anti-IgM (B), or anti-CD40 antibody (C), or loxoribine (D), or CpG (E), or non-CpG (F) for 72 hours. Relative fluorescence unit (RFU) was measured and is expressed as ex vivo cell proliferation.

Mentions: One hypothesis to explain how viral infection can facilitate B cell hyperplasia and lymphoma, is that the viral latent genes render infected B cells hyperresponsive to BCR and Toll-like receptor (TLR) signaling. We showed earlier that purified B cells from KSHV latency mice respond better to lipopolysaccharide (LPS), anti-IgM, and anti-CD40 [29]. As a polyvalent antigen, LPS activates both TLR and BCR signaling [35]. To test the hypothesis that the KSHV latency locus conferred a similar hyperresponsiveness in the Myc background, ex vivo proliferation of splenic B cells was assessed. Splenic CD19+ cells from the Myc/latency mice showed dose-dependent hyperresponsiveness to LPS, but no longer to anti-IgM or anti-CD40 or a TLR7 agonist, loxoribine or a TLR9 agonist, CpG-containing oligonucleotides (Fig 3). In the case of the LPS response, the difference between Myc and Myc/latency was significant to p ≤ 0.05 by ANOVA. The presence of the KSHV transgene increased the response to LPS. The presence of the KSHV transgene dampened the response to BCR crosslinking by anti-IgM antibody. This suggests that the KSHV latency locus augments TLR but not BCR-only or CD40L-only signaling pathways in the context of activated Myc.


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

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

KSHV latency locus confers hyper-responsiveness to LPS in the environment of forced Myc overexpression.Proliferation was evaluated by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into DNA. Splenic B cells from the transgenic (n = 5) and wild-type mice (n = 5) were cultured with varying doses of LPS (A), or anti-IgM (B), or anti-CD40 antibody (C), or loxoribine (D), or CpG (E), or non-CpG (F) for 72 hours. Relative fluorescence unit (RFU) was measured and is expressed as ex vivo cell proliferation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556645&req=5

ppat.1005135.g003: KSHV latency locus confers hyper-responsiveness to LPS in the environment of forced Myc overexpression.Proliferation was evaluated by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into DNA. Splenic B cells from the transgenic (n = 5) and wild-type mice (n = 5) were cultured with varying doses of LPS (A), or anti-IgM (B), or anti-CD40 antibody (C), or loxoribine (D), or CpG (E), or non-CpG (F) for 72 hours. Relative fluorescence unit (RFU) was measured and is expressed as ex vivo cell proliferation.
Mentions: One hypothesis to explain how viral infection can facilitate B cell hyperplasia and lymphoma, is that the viral latent genes render infected B cells hyperresponsive to BCR and Toll-like receptor (TLR) signaling. We showed earlier that purified B cells from KSHV latency mice respond better to lipopolysaccharide (LPS), anti-IgM, and anti-CD40 [29]. As a polyvalent antigen, LPS activates both TLR and BCR signaling [35]. To test the hypothesis that the KSHV latency locus conferred a similar hyperresponsiveness in the Myc background, ex vivo proliferation of splenic B cells was assessed. Splenic CD19+ cells from the Myc/latency mice showed dose-dependent hyperresponsiveness to LPS, but no longer to anti-IgM or anti-CD40 or a TLR7 agonist, loxoribine or a TLR9 agonist, CpG-containing oligonucleotides (Fig 3). In the case of the LPS response, the difference between Myc and Myc/latency was significant to p ≤ 0.05 by ANOVA. The presence of the KSHV transgene increased the response to LPS. The presence of the KSHV transgene dampened the response to BCR crosslinking by anti-IgM antibody. This suggests that the KSHV latency locus augments TLR but not BCR-only or CD40L-only signaling pathways in the context of activated 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