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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1791-1792. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Janz, S. Search for Related Content PubMed Articles by Janz, S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Comment on Shen et al, page 1991 TCL1-induced germinal center B lymphomas in mice Siegfried Janz CENTER FOR CANCER RESEARCH Enforced transgenic expression of the T-cell leukemia/lymphoma 1 oncoprotein, TCL1, in lymphocytes in mice results in a range of B-cell neoplasms that require the germinal center to develop. In the key experiment of the present study, Shen and colleagues use mice that are homozygous for a null allele of Pou2af1 to demonstrate that TCL1-driven malignant B-cell transformation does not take place when the TCL1 transgene is crossed onto the genetic background of OCA-B deficiency. Although TCL1 was originally discovered in patients with T-cell neoplasms, it seems to play an even more prominent role in B-lineage tumors. The mechanism by which TCL1 facilitates the malignant transformation of B lymphocytes is complex and poorly understood. What has been elucidated thus far is that TCL1 augments the activation of the AKT (v-akt murine thymoma viral oncogene homolog) serine/threonine kinase, probably by forming stable heteromeric TCL1-AKT complexes at the inner cell membrane. The resultant enhancement of AKT signaling promotes B-cell proliferation and survival, thus increasing the likelihood of secondary oncogenic mutations and full malignant cell transformation. Stimulation of the protein kinase C–mitogen-activated protein kinase–extracellular signal–regulated kinase (PKC-MAPK-ERK) signaling cascade has also been implicated in TCL1-dependent B-cell transformation, but many details remain unknown. Realizing that a good mouse model of de-regulated TCL1 expression in lymphocytes may be instrumental in advancing our understanding of TCL1-induced lymphoma development, Shen and colleagues took advantage of an Eµ-B29 promoter to express a TCL1 transgene in B cells and T cells in mice. In previous work,1 they used histopathologic criteria to show that Eµ-B29-TCL1 transgenic mice are prone to B-cell lymphomas of germinal-cell (GC) origin, including follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and Burkitt-like lymphoma (BLL). This finding was of great interest, since most common B-lymphocyte neoplasms in humans arise via malignant transformation of GC B lymphocytes—but accurate mouse models of tumors of this sort are scarce. In this issue of Blood, Shen and colleagues recruit expert collaboration from the laboratories of Drs Fred Alt (Harvard Medical School), Bob Roeder (Rockefeller University), and Sandy Morse (National Institute of Allergy and Infectious Diseases [NIAID]) to continue their studies on tumor development in Eµ-B29-TCL1 transgenics. Shen and colleagues report exciting new insights into the target cell (mature B lymphocyte), microenvironment (GC), and mechanism (c-Myc activation, genomic instability, T-cell help) of TCL1-dependent cell transformation. View larger version (33K): [in this window] [in a new window]   Simplified model on TCL1-driven neoplastic development of GC B lymphocytes. Elevated levels of TCL1 in GC B cells increase proliferation, resistance to Fas-dependent apoptosis, and expression of AID (not shown). Full malignant transformation of these cells is strictly dependent upon OCA-B, which is required for the development of GCs in secondary lymphoid tissues. TCL1-transgenic lymphomas, classified as FL, BLL, or DLBCL, exhibit features of genomic instability and contain elevated Myc (not shown).   In the key experiment of the current study, Shen and colleagues use mice that are homozygous for a null allele of Pou2af1 to demonstrate that TCL1-driven malignant B-cell transformation does not take place when the TCL1 transgene is crossed onto the genetic background of OCA-B deficiency. Since Oct coactivator from B cell (OCA-B)–deficient mice are incapable of forming GCs, this result provides definitive genetic evidence that TCL1-induced B lymphomas are dependent on the microenvironment of the GC (see figure). Cytogenetic and molecular analysis of B lymphomas from OCA-B–proficient, TCL1-transgenic mice revealed recurrent chromosomal translocations and an extra copy of the c-Myc containing chromosome 15 (trisomy 15), with corresponding overexpression of the Myc oncoprotein. Further investigation showed that frank lymphoma was preceded by an expansion of TCL1-transgenic B cells that exhibited enhanced resistance to FAS-mediated apoptosis and increased expression of the activation-induced cytidine deaminase (AID). This finding led the authors to propose that elevated AID may be the underlying reason for the observed genomic instability in TCL1-induced lymphomas. The findings reported by Shen and colleagues have important implications for human B-cell neoplasms, in which small-molecule inhibitors of TCL1, particularly its interaction domain with AKT, might be of therapeutic value. The present Eµ-B29-TCL1 transgenic mice provide a promising preclinical model system for the design and testing of these inhibitors, illustrating once again that genetically engineered mouse models of human cancer may ultimately lead to new clinical applications benefiting cancer patients. References Hoyer KK, French SW, Turner DE, et al. Dysregulated TCL1 promotes multiple classes of mature B cell lymphoma. Proc Natl Acad Sci USA. 2002;99: 14392-14397.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Dysregulated TCL1 requires the germinal center and genome instability for mature B-cell transformation Rhine R. Shen, David O. Ferguson, Mathilde Renard, Katrina K. Hoyer, Unkyu Kim, Xingpei Hao, Frederick W. Alt, Robert G. Roeder, Herbert C. Morse, III, and Michael A. Teitell Blood 2006 108: 1991-1998. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Janz, S. Search for Related Content PubMed Articles by Janz, S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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