title: Dysregulated TCL1 requires the germinal center and genome instability for mature B-cell transformation.
abstract: Most lymphomas arise by transformation of germinal center (GC) B cells. TCL1, a proto-oncogene first recognized for its role in T-cell transformation, also induces GC B-cell malignancies when dysregulated in pEmu-B29-TCL1 transgenic (TCL1-tg) mice. Clonal B-cell lymphomas develop from polyclonal populations with latencies of 4 months or more, suggesting that secondary genetic events are required for full transformation. The goals of this study were to determine the GC-related effects of TCL1 dysregulation that contribute to tumor initiation and to identify companion genetic alterations in tumors that function in disease progression. We report that compared with wild-type (WT) cells, B cells from TCL1-tg mice activated in a manner resembling a T-dependent GC reaction show enhanced resistance to FAS-mediated apoptosis with CD40 stimulation, independent of a B-cell antigen receptor (BCR) rescue signal. Mitogenic stimulation of TCL1-tg B cells also resulted in increased expression of Aicda. These GC-related enhancements in survival and Aicda expression could underlie B-cell transformation. Supporting this notion, no B-cell lymphomas developed for 20 months when TCL1-tg mice were crossed onto an Oct coactivator from B cell (OCA-B)-deficient background to yield mice incapable of forming GCs. Spectral karyotype analyses showed that GC lymphomas from TCL1-tg mice exhibit recurrent chromosome translocations and trisomy 15, with corresponding MYC overexpression. We conclude that pEmu-B29-TCL1 transgenic B cells primed for transformation must experience the GC environment and, for at least some, develop genome instability to become fully malignant.
authors.affiliation: Department of Pathology, David Geffen School of Medicine, University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA.
authors.forename: Rhine R
authors.initials: RR
authors.lastname: Shen
authors.forename: David O
authors.initials: DO
authors.lastname: Ferguson
authors.forename: Mathilde
authors.initials: M
authors.lastname: Renard
authors.forename: Katrina K
authors.initials: KK
authors.lastname: Hoyer
authors.forename: Unkyu
authors.initials: U
authors.lastname: Kim
authors.forename: Xingpei
authors.initials: X
authors.lastname: Hao
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Michael A
authors.initials: MA
authors.lastname: Teitell
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019013:CD40 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D003564:Cytidine Deaminase / Q000378:metabolism; D053222:Fas Ligand Protein; D005260:Female; D015870:Gene Expression; D016259:Genes, myc; D042822:Genomic Instability; D018858:Germinal Center / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000235:genetics / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011519:Proto-Oncogenes; D048069:Tumor Necrosis Factors / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D019013:CD40 Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse; D048069:Tumor Necrosis Factors; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase