title: PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas.
abstract: Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (∼40%) and/or mutations disrupting autoregulation (∼16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 transgene, we hypothesized that mutated genes are likely to play an important cooperative role in BCL6-associated lymphoma development. We used retroviral insertional mutagenesis in an effort to identify which genes cooperate with BCL6 in lymphomagenesis in our BCL6 transgenic mice. We identified PIM1 as the most frequently recurring cooperating gene in our murine BCL6-associated lymphomas (T- and B-cell types), and we observed elevated levels of PIM1 mRNA and protein expression in these neoplasms. Further, immunohistochemical staining, which was performed in 20 randomly selected BCL6-positive human B- and T-cell lymphomas, revealed concurrent expression of BCL6 and PIM1 in these neoplasms. As PIM1 encodes a serine/threonine kinase, PIM1 kinase inhibition may be a promising therapy for BCL6/PIM1-positive human lymphomas.
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL 60637, USA. erly.baron@uchospitals.edu
authors.forename: Beverly W
authors.initials: BW
authors.lastname: Baron
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Hyjek
authors.forename: Juraj
authors.initials: J
authors.lastname: Bies
authors.forename: Poluru L
authors.initials: PL
authors.lastname: Reddy
authors.forename: Jingfang
authors.initials: J
authors.lastname: Dong
authors.forename: Loren
authors.initials: L
authors.lastname: Joseph
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thirman
authors.forename: Kristen
authors.initials: K
authors.lastname: Wroblewski
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Baron
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology*; D051560:Proto-Oncogene Proteins c-bcl-6; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D016019:Survival Analysis
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1