KSHV-encoded vIL-6 collaborates with deregulated c-Myc to drive plasmablastic neoplasms in mice

T R Rosean; C J Holman; V S Tompkins; X Jing; M D Krasowski; S Rose-John; S Janz

doi:10.1038/bcj.2016.6

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KSHV-encoded vIL-6 collaborates with deregulated c-Myc to drive plasmablastic neoplasms in mice

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KSHV-encoded vIL-6 collaborates with deregulated c-Myc to drive plasmablastic neoplasms in mice

T R Rosean, C J Holman, V S Tompkins, X Jing, M D Krasowski, S Rose-John and S Janz

Blood Cancer Journal, Vol.6, pp.398-398

02/26/2016

DOI: 10.1038/bcj.2016.6

PMCID: PMC4771969

PMID: 26918362

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Published (Version of record)Blood Cancer J. 2016 Feb; 6(2): e398.

Abstract

The mechanism by which Kaposi sarcoma (KS)-associated herpesvirus (KSHV), now recognized as human HV-8 (HHV-8), drives cancer is poorly understood.1 In addition to KS, the virus causes life-threatening pathologies of the mature B-lymphocyte lineage,2 including multi-centric Castleman's disease (MCD),3 diffuse large B-cell lymphoma evolving from MCD (MCD-DLBCL)4 and primary effusion lymphoma (PEL).5 These B-cell disorders are a significant public health concern because KSHV is frequently associated with HIV, which by itself increases the risk of developing B-lymphoma by ~2 orders of magnitude. In addition, the broad implementation of highly effective antiretroviral therapy has inadvertently caused a spike in lymphoma-related morbidity and mortality due to increased survival of HIV patients. Here, we took advantage of the laboratory mouse to enhance our understanding of KSHV-dependent pathophysiology in the B-lymphocyte lineage. Specifically, we evaluated the hypothesis that a KSHV-encoded cytokine, viral interleukin-6, hereafter called vIL-6, may be a driver of the transformation of B-lymphocytes to a malignant state. Our experimental strategy included the refinement of a recently developed C57BL/6 (B6) mouse model of constitutive, H2-K promoter-driven, transgenic (TG) vIL-6 expression6 by making two critical changes. First, we backcrossed the vIL6 transgene from the genetic background of B6 onto BALB/c (C), an inbred strain of mice that is hyper-susceptible to malignant plasma cell tumors, such as inflammation-dependent peritoneal plasmacytoma.7 Second, we intercrossed the newly generated C.vIL6 congenic mice with C.iMycΔEμ mice, a gene-insertion model of the chromosomal translocation T(12;15) that results in the deregulated expression of the cellular oncogene Myc in the B-cell lineage. We found that single-TG C.vIL6 mice are prone to a severe and sometimes fatal MCD-like disease, whereas double-TG C.vIL6iMyc mice invariably developed aggressive plasmablastic neoplasms that exhibited striking clinical and histopathological similarities to human PEL, plasmablastic lymphoma (PBL) and immunoglobulin (Ig)-producing, extramedullary plasmablastic plasma cell myeloma (PBM). Article summarizes new findings.

Pathology

OAfund

Kaposi scarcoma

kaposi sarcoma-associated herpesvirus

KSHV

HV-8

HHV-8

Details

Title: Subtitle: KSHV-encoded vIL-6 collaborates with deregulated c-Myc to drive plasmablastic neoplasms in mice
Creators: T R Rosean - University of Iowa
C J Holman - University of Iowa
V S Tompkins - University of Iowa
X Jing - University of Iowa
M D Krasowski - University of Iowa
S Rose-John - Christian-Albrechts-University
S Janz - University of Iowa
Resource Type: Letter/Communication
Publication Details: Blood Cancer Journal, Vol.6, pp.398-398
DOI: 10.1038/bcj.2016.6
PMID: 26918362
PMCID: PMC4771969
NLM abbreviation: Blood Cancer J
ISSN: 2044-5385
Number of pages: 5
Grant note: This work was supported in part by NIH Pre-doctoral Training Grant T32 AI007485 to TRR; NIH Hematology Training Grant T32 HL007344 to VST; R01CA151354 from the NCI to SJ; and NCI Core Grant P30CA086862 in support of the Holden Comprehensive Cancer Center.
Language: English
Date published: 02/26/2016
Academic Unit: Pathology; Holden Comprehensive Cancer Center
Record Identifier: 9983557566202771

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