Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia

Eun Sung Park,Fenghuang Zhan,Ju-Seog Lee,James D Owens,Shalu Gupta,Hongyang Wang,Michael Potter,J Frederic Mushinski,Hyun Goo Woo,John D Shaughnessy,Siegfried Janz

doi:10.1186/1471-2164-8-302

Abstract

BackgroundTo elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B-cell lymphomas and six subtypes of pristane-induced mouse plasma cell tumors, three of which developed much earlier than the others.ResultsUnsupervised hierarchical cluster analysis exhibited two main sub-clusters of samples: a B-cell lymphoma cluster and a plasma cell tumor cluster with subclusters reflecting mechanism of induction. This report represents the first step in using global gene expression to investigate molecular signatures related to the role of cooperating oncogenes in a model of Myc-induced carcinogenesis. Within a single subgroup, e.g., ABPCs, plasma cell tumors that contained typical T(12;15) chromosomal translocations did not display gene expression patterns distinct from those with variant T(6;15) translocations, in which the breakpoint was in the Pvt-1 locus, 230 kb 3' of c-Myc, suggesting that c-Myc activation was the initiating factor in both. When integrated with previously published Affymetrix array data from human multiple myelomas, the IL-6-transgenic subset of mouse plasma cell tumors clustered more closely with MM1 subsets of human myelomas, slow-appearing plasma cell tumors clustered together with MM2, while plasma cell tumors accelerated by v-Abl clustered with the more aggressive MM3-MM4 myeloma subsets. Slow-appearing plasma cell tumors expressed Socs1 and Socs2 but v-Abl-accelerated plasma cell tumors expressed 4–5 times as much. Both v-Abl-accelerated and non-v-Abl-associated tumors exhibited phosphorylated STAT 1 and 3, but only v-Abl-accelerated plasma cell tumors lost viability and STAT 1 and 3 phosphorylation when cultured in the presence of the v-Abl kinase inhibitor, STI-571. These data suggest that the Jak/Stat pathway was critical in the transformation acceleration by v-Abl and that v-Abl activity remained essential throughout the life of the tumors, not just in their acceleration. A different pathway appears to predominate in the more slowly arising plasma cell tumors.ConclusionGene expression profiling differentiates not only B-cell lymphomas from plasma cell tumors but also distinguishes slow from accelerated plasma cell tumors. These data and those obtained from the sensitivity of v-Abl-accelerated plasma cell tumors and their phosphorylated STAT proteins indicate that these similar tumors utilize different signaling pathways but share a common initiating genetic lesion, a c-Myc-activating chromosome translocation.

Highlights

To elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B-cell lymphomas and six subtypes of pristane-induced mouse plasma cell tumors, three of which developed much earlier than the others
Gene expression profiling differentiates B-cell lymphomas from plasma cell tumors and distinguishes slow from accelerated plasma cell tumors. These data and those obtained from the sensitivity of v-Abl-accelerated plasma cell tumors and their phosphorylated STAT proteins indicate that these similar tumors utilize different signaling pathways but share a common initiating genetic lesion, a c-Myc-activating chromosome translocation
Infection with retroviruses containing oncogenes, e.g., Abelson Virus (v-Abl [2]), J3V1 virus (v-Raf plus vMyc [3]), RIM virus (v-Ha-Ras plus c-Myc [4]), ABLMYC Virus (v-Abl plus c-Myc [5]), accelerates plasma cell tumors (PCTs) formation, producing ABPC, J3PCs, RIMPCs and ABLMYCPCs, respectively, in as little as 12 days. It has never been tested whether continued activity of these accelerating oncogenes was required subsequent to completion of transformation. iMycEμ (Myc/IgH-knockin) BALB/c mice and interleukin 6 (IL-6)-transgenic BALB/c mice develop intraperitoneal PCTs iMycEμ PCs [6] and KiPCs [7], respectively, at a slightly accelerated rate following pristane injection

Summary

Introduction

To elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B-cell lymphomas and six subtypes of pristane-induced mouse plasma cell tumors, three of which developed much earlier than the others. Infection with retroviruses containing oncogenes, e.g., Abelson Virus (v-Abl [2]), J3V1 virus (v-Raf plus vMyc [3]), RIM virus (v-Ha-Ras plus c-Myc [4]), ABLMYC Virus (v-Abl plus c-Myc [5]), accelerates PCT formation, producing ABPC, J3PCs, RIMPCs and ABLMYCPCs, respectively, in as little as 12 days (see Figure 1A and Table 1). It has never been tested whether continued activity of these accelerating oncogenes was required subsequent to completion of transformation. Other forms of B-cell lymphomas (BCL) appear in the lymph nodes of iMyc mice, BCLEμ [9] and BCLCα [10]

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