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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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NEOPLASIA
Potentially oncogenic B-cell activation–induced smaller isoforms of FOXP1 are highly expressed in the activated B cell–like subtype of DLBCL
Philip J. Brown1,
Sally L. Ashe1,
Ellen Leich2,
Christof Burek2,
Sharon Barrans3,
James A. Fenton3,
Andrew S. Jack3,
Karen Pulford1,
Andreas Rosenwald2, and
Alison H. Banham1
1 Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;
2 Institute of Pathology, University of Würzburg, Würzburg, Germany; and
3 Haematological Malignancy Diagnostic Service (HMDS), Leeds General Infirmary, Leeds, United Kingdom
The FOXP1 forkhead transcription factor is targeted by recurrent chromosome translocations in several subtypes of B-cell non-Hodgkin 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 2 smaller, 60 to 65 kDa, FOXP1 isoforms in all 5 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 center–derived DLBCLs. ABC-like DLBCL-derived cell lines were observed to express 2 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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