Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas

Abstract

Oncogenes involved in recurrent chromosomal translocations serve as diagnostic markers and therapeutic targets in hematopoietic tumors. In contrast to myeloid and B-cell neoplasms, translocations in peripheral T-cell lymphomas (PTCLs) are poorly understood. Here, we identified recurrent translocations involving the multiple myeloma oncogene-1/interferon regulatory factor-4 (IRF4) locus in PTCLs. IRF4 translocations exist in myeloma and some B-cell lymphomas, but have not been reported earlier in PTCLs. We studied 169 PTCLs using fluorescence in situ hybridization and identified 12 cases with IRF4 translocations. Two cases with t(6;14)(p25;q11.2) had translocations between IRF4 and the T-cell receptor-alpha (TCRA) locus. Both were cytotoxic PTCLs, unspecified (PTCL-Us) involving bone marrow and skin. In total, 8 of the remaining 10 cases were cutaneous anaplastic large-cell lymphomas (ALCLs) without TCRA rearrangements (57% of cutaneous ALCLs tested). These findings identified IRF4 translocations as a novel recurrent genetic abnormality in PTCLs. Cytotoxic PTCL-Us involving bone marrow and skin and containing IRF4/TCRA translocations might represent a distinct clinicopathologic entity. Translocations involving IRF4 but not TCRA appear to occur predominantly in cutaneous ALCLs. Detecting these translocations may be useful in lymphoma diagnosis. Further, due to its involvement in translocations, MUM1/IRF4 protein may play an important biologic role in some PTCLs, and might represent a possible therapeutic target.

Figure 1

Peripheral T-cell lymphomas, unspecified (PTCL-Us) with IRF4/TCRA translocations involving bone marrow and skin. (a) Diffuse infiltration of bone marrow (75% involvement) in a 67 year-old male (Case 1; H&E, x 4); reticulin fibrosis is present (inset, x 40). (b) Medium to large tumor cells with plasma cells in the background (H&E, x 40; inset, x 100). Tumor cells are positive for (c) CD3, (d) TIA1, (e) and MUM1/IRF4 (x 40; inset, x 100). (f) Skin biopsy from the same patient 4 mos later. Compared to the bone marrow, the tumor cells are more uniformly large and pleomorphic, and are accompanied by apoptotic debris without admixed plasma cells (H&E, x 40; inset, x 100). (g) Diffuse infiltration of bone marrow (40% involvement) in a 71 year-old male (Case 2; H&E, x 4; reticulin, inset, x 40). (h) Mostly medium-sized tumor cells with plasma cells in the background (H&E, x 40; inset, x 100). (i) Tumor cells are positive for MUM1/IRF4 (x 40; inset, x 100). (j) Karyotype shows t(6;14)(p25;q11.2). (k) Dual-fusion fluorescence in situ hybridization (D-FISH) shows IRF4/TCRA fusion signals (arrows).

Figure 2

Anaplastic large-cell lymphomas (ALCLs) with IRF4 translocations. (a) Primary cutaneous ALCL (C-ALCL), 48 year-old female (case 3). Medium to large tumor cells with admixed histiocytes (H&E, x 40; inset, x 100). (b) Lymph node involvement, same patient, 10 years later. Confluent sheets of large “hallmark” cells (H&E, x 40; inset, x 100). (c) C-ALCL, 67 year-old male (case 4; H&E, x 20; inset, x 100). (d) Lymph node involvement, same patient, 7 mos later (H&E, x 40; inset, x 100). Both biopsies show sheets of “hallmark” cells. (e) C-ALCL, 89 year-old female (case 5), showing positivity for (f) CD30 and (g) MUM1/IRF4 (x 10; insets, x 100). (h) Breakapart fluorescence in situ hybridization (BAP-FISH) shows separation of red and green signals flanking the IRF4 gene locus (arrows). (i) Systemic ALK-negative ALCL, cervical lymph node, 79 year-old male (case 12). Large “hallmark” cells surround a residual reactive follicle (lower left; H&E, x 40; inset, x 100).