Diminished Nuclear Expression of the T-Lineage Transcription Factor BCL11B in Peripheral T-Cell Lymphomas Correlates with Subtype and Loss of CD3 Expression.
Nazan Ozsan, Mark E Law, Steven C Ziesmer, Stephen M Ansell, Ahmet Dogan, Andrew L Feldman. Ege University, Izmir, Turkey; Mayo Clinic, Rochester, MN
Background: Peripheral T-cell lymphomas (PTCLs) often show loss of T-lineage antigens, but the mechanism of this loss is poorly understood. Three recent reports (Science 2010;310:85-96) showed the transcription factor BCL11B is critical for T-lineage development, and its absence was associated with NK differentiation and loss of T-antigen expression. We hypothesized that PTCL subtypes associated with T-antigen loss and/or NK phenotype would show diminished expression of BCL11B.
Design: We studied PTCLs from 183 patients (113M, 70F; mean age, 59 y), including 64 PTCLs, NOS; 48 angioimmunoblastic (AITLs); 46 anaplastic large cell (ALCLs); 11 extranodal NK/T-cell, nasal type (NKTLs); 7 cutaneous (CTCLs); and 7 cytotoxic (ctPTCLs). Immunohistochemistry for BCL11B (Abcam, 1:5000) was scored for nuclear (nuc) and cytoplasmic (cyt) tumor cell staining (1 = <30%; 2 = 30-80%; 3 = >80%) and stratified by CD3 expression (30% cutoff). FISH was performed using a BCL11B breakapart probe.
Results: Mean nuclear staining scores were lowest in ALCLs (1.4) and NKTLs (1.5), followed by: PTCLs, NOS (1.8); AITLs (1.8); ctPTCLs (2.1), and CTCLs (2.3). The reverse was true for cytoplasmic staining scores (see figure). These differences were significant, e.g. ALCL+NKTL vs all others (t test: nuc, p=0.00004; cyt, p=1x10-7) and ALCL vs PTCL, NOS (nuc, p=0.002; cyt, p=3x10-6). CD3-negative PTCLs had lower nuclear and higher cytoplasmic scores than CD3-positive PTCLs (nuc, 1.4 vs 1.8, p=0.0008; cyt, 2.0 vs 1.5, p=0.001). No BCL11B translocations were identified, but 4 PTCLs, NOS had >3 copies of BCL11B.
Conclusions: Diminished nuclear expression of the T-lineage transcription factor BCL11B is most common in ALCLs and NKTLs, and correlates with loss of CD3 expression in PTCLs. Cytoplasmic BCL11B is inversely proportional to nuclear expression, suggesting these differences may derive from failure of nuclear localization of BCL11B. Particularly, diminished nuclear BCL11B may cause the frequent T-antigen loss seen in ALCLs. Since BCL11B is antiapoptotic and associated with chemoresistance in malignant T cells, decreased nuclear expression in ALCLs might contribute to their favorable prognosis relative to other PTCLs.
Tuesday, March 1, 2011 8:15 AM
Platform Session: Section B, Tuesday Morning