Nuclear overexpression of lymphoid-enhancer-binding factor 1 identifies chronic lymphocytic leukemia/small lymphocytic lymphoma in small B-cell lymphomas

Abstract

Lymphoid-enhancer-binding factor 1 (LEF1), coupling with b-catenin, functions as a key nuclear mediator of WNT/b-catenin signaling, which regulates cell proliferation and survival. LEF1 has an important role in lymphopoiesis, and is normally expressed in T and pro-B cells but not mature B cells. However, gene expression profiling demonstrates overexpression of LEF1 in chronic lymphocytic leukemia, and knockdown of LEF1 decreases the survival of the leukemic cells. So far, the data on LEF1 expression in B-cell lymphomas are limited. This study represents the first attempt to assess LEF1 by immunohistochemistry in a large series (290 cases) of B-cell lymphomas. Strong nuclear staining of LEF1 was observed in virtually all neoplastic cells in 92 of 92 (100%) chronic lymphocytic leukemia/small lymphocytic lymphomas including two CD5À cases, with strongest staining in cells with Richter's transformation. LEF1 also highlighted the morphologically inconspicuous small lymphocytic lymphoma component in three composite lymphomas. All 53 mantle cell lymphomas, 31 low-grade follicular lymphomas and 31 marginal zone lymphomas, including 3 CD5 þ cases, were negative. In 12 grade 3 follicular lymphomas, LEF1 was positive in a small subset (5-15%) of cells. Diffuse large B-cell lymphoma, however, demonstrated significant variability in LEF1 expression with overall positivity in 27 of 71 (38%) cases. Our results demonstrate that nuclear overexpression of LEF1 is highly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, and may serve as a convenient marker for differential diagnosis of small B-cell lymphomas. The expression of b-catenin, the coactivator of LEF1 in WNT signaling, was examined in 50 chronic lymphocytic leukemia/small lymphocytic lymphomas, of which 44 (88%) showed negative nuclear staining. The findings of universal nuclear overexpression of LEF1 but lack of nuclear b-catenin in the majority of chronic lymphocytic leukemia/small lymphocytic lymphoma suggest that the pro-survival function of LEF1 in this disease may be independent of WNT/b-catenin signaling.

High expression and nuclear localization of β-catenin in diffuse large B-cell lymphoma

“…The Wnt/β-catenin pathway plays an important role in the progression of leukemia, myeloma (16)(17)(18)(19) and several subtypes of lymphoma, such as Epstein-Barr virus (EBV)-positive Burkitt's lymphoma (BL) (20)(21)(22), mantle cell lymphoma (MCL) (23)(24)(25), cutaneous lymphoma (26), extranodal marginal zone lymphoma (27), ALK-positive anaplastic large cell lymphoma (28), small B-cell lymphoma (29) and DLBCL (9,30). Scientists demonstrated that ethacrynic acid (EA) and the antifungal agent ciclopirox olamine (cic) inhibited the Wnt/β-catenin signaling in OPM-2 myeloma and three lymphoma cell lines (OCI-LY8-LAM-53, SU-DHL-4 and Raji) in vitro, leading to apoptosis and a significant decrease in the viability of lymphoma and its cell lines (30).…”

A Possible Risk Gene for B-cell Chronic Lymphocytic Leukemia: NRIP1

“…Many studies indicated that INPP5F and LEF1 may have a role in the therapeutic strategies of CLL [22,23] . More potential connections between these genes and B-CLL could be identified from the B-CLL_ Meta database (see B-CLL_Meta → NRIP1, INPP5F and LEF1), which is available in the open source 'Bioinformatics Database' (http://database.gousinfo.…”

A low-grade B-cell lymphoma with prolymphocytic/paraimmunoblastic proliferation and IRF4 rearrangement

“…Cytogenetic analyses were successful in case 1, 46XX,t(2;6)(p11.2;p25) [10]/46XX,t(1;11)(q21;q23) [1]/46XX [9], and case 3, 4 6 X Y, t ( 2 ; 6 ) ( p 1 2 ; p 2 5 ) [ 1 ] / 4 6 , s l , -Y, -4 , -8 , -9 , -9,add(11)(q23),+5mar[1]/46XY [11]. No evidence of rearrangement in BCL2, BCL6, MYC, and CCND1 was obtained in the present cases, whereas in previous cases, 2 2 The present and previous findings indicate that IRF4 rearrangement may be related to the development of low-grade and primary high-grade lymphomas and that some IRF4-rearranged low-grade lymphomas may progress to high-grade lymphomas.…”