title: Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  Unsupervised 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.
  
  
  CONCLUSIONS
  Gene 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.
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. espark@mdanderson.org
authors.forename: Eun Sung
authors.initials: ES
authors.lastname: Park
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.forename: Shalu
authors.initials: S
authors.lastname: Gupta
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Hyun Goo
authors.initials: HG
authors.lastname: Woo
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.forename: James D
authors.initials: JD
authors.lastname: Owens
authors.forename: Michael
authors.initials: M
authors.lastname: Potter
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.forename: J Frederic
authors.initials: JF
authors.lastname: Mushinski
mesh_terms: D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016313:Genes, abl; D016259:Genes, myc; D006801:Humans; D000068877:Imatinib Mesylate; D016393:Lymphoma, B-Cell / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009101:Multiple Myeloma / Q000235:genetics; D054219:Neoplasms, Plasma Cell / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000235:genetics
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D050791:STAT Transcription Factors; D000068877:Imatinib Mesylate