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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.
Highlights
Myc encodes a multifunctional protein which is involved in many biological functions, including transcriptional control, cell cycle, signal transduction, oncogenesis, and development
We already showed that Kaposi sarcoma-associated herpesvirus (KSHV) latency locus transgenic mice consistently develop B cell hyperplasia
To find out possible host contributions to lymphomagenesis we evaluated the Myc oncogene
Summary
Myc encodes a multifunctional protein which is involved in many biological functions, including transcriptional control, cell cycle, signal transduction, oncogenesis, and development (reviewed in [1]). Some cases of DLBCL, such as anaplastic lymphoma kinase (ALK) positive large B-cell lymphoma do not carry Myc translocation per se, but overexpress Myc protein [3,4]. This suggests that deregulated expression of the Myc protein by any means contributes to B cell lymphomagenesis. Transgenic mice expressing a translocated Myc gene from a human BL cell line under the Igλ light chain regulatory sequences readily developed lymphomas [8], whereas transgenic mice with a specific, single copy targeted insertion into the Cα of the IgH locus (iMycCα mouse), which mimic the t(8;14) in BL, developed B cell lymphomas with very low incidence [7]. The phenotypes of Myc mouse models range from moderate to fully penetrant, aggressive lymphomagenesis depending on the particulars of the transgene regulatory context, each mimicking different types and/or stages of lymphomagenesis
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