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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2816-2824.
Prepublished online as a Blood First Edition Paper on December 12, 2007; DOI 10.1182/blood-2007-09-115113.
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Submitted September 26, 2007
Accepted December 7, 2007
Potentially oncogenic B-cell activation induced smaller isoforms of FOXP1 are highly expressed in the activated B-cell-like subtype of DLBCL
Philip J Brown, Sally L Ashe, Ellen Leich, Christof Burek, Sharon Barrans, James A Fenton, Andrew S Jack, Karen Pulford, Andreas Rosenwald, and Alison H Banham*
Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany
Haematological Malignancy Diagnostic Service (HMDS), Leeds General Infirmary, Leeds, United Kingdom
* Corresponding author; email: alison.banham{at}ndcls.ox.ac.uk.
The FOXP1 forkhead transcription factor is targeted by recurrent chromosome translocations in several subtypes of B-cell non-Hodgkin's lymphomas, where high-level FOXP1 protein expression has been linked to a poor prognosis. Western blotting studies of diffuse large B-cell lymphoma (DLBCL) cell lines unexpectedly identified the atypical high-level expression of two smaller, 60-65kDa, FOXP1 isoforms in all five of those with the activated B-cell (ABC)-like DLBCL subtype and in a subgroup of primary DLBCL. The anti-FOXP1 (JC12) monoclonal antibody cannot distinguish FOXP1 isoforms by immunohistochemistry, a finding that may be clinically relevant as high-level expression of the full-length FOXP1 protein was observed in some germinal centre-derived DLBCL. ABC-like DLBCL-derived cell lines were observed to express two, novel, alternatively spliced FOXP1 mRNA isoforms, encoding N-terminally truncated proteins. These transcripts and the smaller protein isoforms were induced as a consequence of normal B-cell activation, which thus represents an additional mechanism for up-regulating FOXP1 expression in lymphomas. The expression of potentially oncogenic smaller FOXP1 isoforms may resolve the previously contradictory findings that FOXP1 represents a favorable prognostic marker in breast cancer and an adverse risk factor in B-cell lymphomas.
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