Enhancer mutations of Akv murine leukemia virus inhibit the induction of mature B-cell lymphomas and shift disease specificity towards the more differentiated plasma cell stage

Abstract

This study investigates the role of the proviral transcriptional enhancer for B-lymphoma induction by exogenous Akv murine leukemia virus. Infection of newborn inbred NMRI mice with Akv induced 35% plasma cell proliferations (PCPs) (consistent with plasmacytoma), 33% diffuse large B-cell lymphomas, 25% follicular B-cell lymphomas and few splenic marginal zone and small B-cell lymphomas. Deleting one copy of the 99-bp proviral enhancer sequence still allowed induction of multiple B-cell tumor types, although PCPs dominated (77%). Additional mutation of binding sites for the glucocorticoid receptor, Ets, Runx, or basic helix-loop-helix transcription factors in the proviral U3 region, however, shifted disease induction to almost exclusively PCPs, but had no major influence on tumor latency periods. Southern analysis of immunoglobulin rearrangements and ecotropic provirus integration patterns showed that many of the tumors/cell proliferations induced by each virus were polyclonal. Our results indicate that enhancer mutations weaken the ability of Akv to induce mature B-cell lymphomas prior to the plasma cell stage, whereas development of plasma cell proliferations is less dependent of viral enhancer strength.

Loss of MicroRNA Targets in the 3′ Untranslated Region as a Mechanism of Retroviral Insertional Activation of Growth Factor Independence 1

“…The tumors assayed in this study originated from previously published and unpublished pathogenicity studies involving mainly wt SL3-3 (51) and Akv (43,69), as well as SL3-3 and Akv mutated in the host transcription factor binding sites nuclear factor 1 (NF1) (18), Runx (19,70), and glucocorticoid response element (17,69) and the basic helix-loop-helix motifs E gre and E a/s (17,69). A panel of tumors originated from experimental studies of SL3-3 with replaced envelope and integrase sequences from SL3-2 and Akv, respectively (unpublished data).…”

“…Tumors originated from previously published (17,18,19,20,27,43,45,51,69,70) and unpublished pathogenicity studies of wt and enhancer mutated SL3-3, Akv, and Reilly-Finkel-Biskis (RFB) MLVs. Large-scale analysis of integrated retroviruses, performed by a splinklerette-based PCR method described previously (78), was able to identify 120 wt and enhancer-mutated SL3-3 integrations in the genomic region carrying Gfi1 from a total of 790 SL3-3 tags.…”

“…c NMRI-i mice were infected with wt SL3-3 (51), Akv (43,69), and RFB (unpublished data) MLVs as well as several SL3-3 and Akv mutants with mutations in host transcription factor binding sites: Runx (19,70), UCR (reference 45 and unpublished data), E gre and E a/s (17,69), Turbo (2⌬18-3) (20,51), glucocorticoid response element (17,70), SL3-2Env (SL3-3 envelope replaced with SL3-2 envelope) (unpublished data), AkvIN (SL3-3 integrase replaced with Akv integrase) (unpublished data), an Akv1-99 (single enhancer repeat variant of Akv) (43).…”

“…The major determinant of MLV latency and disease specificity is the retroviral enhancer in the U3 region of the MLV long terminal repeat (LTR) (3,5,9,17,19,24,37,38,50,52,69,70,71). It comprises conserved areas which hold densely packed binding sites for several host transcription factors, including Runx, NF-1, Ets, c-Myb, the glucocorticoid response element, and basic helix-loop-helix factors.…”

Control of Pathogenicity and Disease Specificity of a T-Lymphomagenic Gammaretrovirus by E-Box Motifs but Not by an Overlapping Glucocorticoid Response Element

“…Notably, no secondary enhancer mutations were found in any Akv enhancer mutant-induced tumor, which also is in contrast to the results of the SL3-3 study. It is unclear why the Akv model differs from the SL3-3 model; however, several features of the former point to the importance of an immunostimulatory component in which the overall viral load as well as insertional mutagenesis plays a role (56).…”