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 previously 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. Eight of the remaining ten cases were cutaneous 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.

Mucosal CD30-positive T-cell lymphoproliferations of the head and neck show a clinicopathologic spectrum similar to cutaneous CD30-positive T-cell lymphoproliferative disorders

“…Rearrangements of 6p25.3 are recurrent in ALK-negative anaplastic large cell lymphomas and are most common in primary cutaneous anaplastic large cell lymphoma, where they are seen in about 28% of cases. 8,[23][24][25] This finding is an additional feature shared between patients with primary mucosal CD30-positive T-cell lymphoproliferations and primary cutaneous cases. A 6p25.3 rearrangement also was seen in a patient with orbital disease (case 15) but unfortunately staging data were not available.…”

“…PCR product fragments Fluorescence in situ hybridization (FISH) was performed on all cases for which adequate material was available using a breakapart probe for the DUSP22-IRF4 locus on 6p25.3, as described previously. 8 Briefly, DNA from bacterial artificial chromosomes CTD-2308G5 (telomeric) or RP11-164H16 (centromeric) was labeled with Texas ReddUTP (Molecular Probes, Invitrogen) or SpectrumGreen-dUTP (Abbott Molecular, Des Plaines, IL, USA), respectively. Paraffin-embedded tissue sections were digested in 0.4% pepsin, hybridized with probe, washed, counterstained with 4 0 ,6-diamidino-2-phenylindole dihydrochloride and analyzed by a microscopist (MEL) using parameters and normal thresholds described previously.…”

“…Paraffin-embedded tissue sections were digested in 0.4% pepsin, hybridized with probe, washed, counterstained with 4 0 ,6-diamidino-2-phenylindole dihydrochloride and analyzed by a microscopist (MEL) using parameters and normal thresholds described previously. 8 …”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…So far, no other genetic alterations (e.g. ITK-SYK translocation [52], IRF4 rearrangements [53], abnormalities, or deletions in chromosome 6q, 7q, or 9q [54–56]) have been linked to diagnosis, complicating clinical decisions in the treatment of PTCL patients. Moreover, combined chemotherapy (CHOP; Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone; or CHOEP with Etoposide) often results initially in favorable response rates, however relapses and refractory disease are frequently observed [45,57].…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…In contrast, the TCR gene loci, while involved in recurrent chromosomal translocations in precursor T-cell lymphoblastic leukemias/ lymphomas, are rarely involved in recurrent translocations in mature T-cell lymphoproliferative disorders [65,66]. With the exception of translocations involving the interferon regulatory factor 4 (IRF4) gene (also known as MUM1) in a subset of cutaneous anaplastic large cell lymphomas, recurrent chromosomal translocations are infrequently observed in CTCL [67][68][69][70][71]. Despite this, a number of signaling pathways regulating cell-cycle progression and survival have been implicated in CTCL pathogenesis.…”