Deregulation of NF-κB, ie, a useful PMBL marker

In this issue of Blood, Mansouri et al¹  report on the distribution of NFKBIE aberrations in lymphoid malignancies and suggest they play an important role in lymphomagenesis. They demonstrate a high frequency of NFKBIE deletions in primary mediastinal B-cell lymphoma (PMBL) and report that they predict for poor outcomes in this population.

Historically considered a diffuse large B-cell lymphoma subtype, PMBL is now considered a distinct entity, commonly presenting with bulky anterior mediastinal masses and predominantly occurring in females during their third or fourth decade of life.²  The prognosis is relatively favorable. However, controversies regarding the treatment of these patients remain, including the optimal chemotherapeutic regimen and which patients require consolidative radiation.

Enhanced signaling through the NF-κB pathway is a common hallmark in the pathogenesis of the lymphomas and is particularly important in diffuse large B-cell lymphoma (see figure). Stimulation through tumor necrosis factor receptors drives cellular proliferation, differentiation and survival as part of normal biologic processes including the development and maturation of B lymphocytes.^3,4  Pathway activation is tightly controlled by the IκB proteins, functioning as negative regulators at the posttranslational level. Deregulation has been observed at multiple levels within the canonical and alternative pathways. In PMBL, more common defects include mutation or deletion of the tumor suppressor TNFAIP3, which encodes A20, as well as REL amplification.

In the report by Mansouri et al, the investigators screened 1460 lymphoma patients for aberrations in the NFKBIE gene that normally functions to encode the negative regulator IκBε. This builds on previous work revealing a novel genetic basis for NF-κB activation. A 7% incidence of a NFKBIE frameshift deletion was reported in a cohort of 315 patients with chronic lymphocytic leukemia.⁵  Functionally, these patients had reduced IκBε protein levels, reduced interactions with p65, and a subsequent increase in nuclear p65 levels. Consistent with increased NF-κB signaling, these patients demonstrated inferior outcomes. Further, the aberrations in the NFKBIE gene were an independent predictor of outcome in multivariate analysis in the group with unmutated immunoglobulin heavy chain variable region genes. In the present report, the investigators identified 86 (5.8%) NFKBIE mutations, the majority of which exhibited the previously described 4-bp deletion, in a heterogeneous group of lymphoma patients. Of 203 patients with PMBL, 22.7% had this deletion. The investigators additionally identified NFKBIE mutations in 4 of 11 Hodgkin lymphoma cases, consistent with the previously described overlapping molecular features between these malignancies.⁶  In the PMBL patients, the NFKBIE deletion was associated with poor responses to chemotherapy and an inferior overall survival, results that again remained significant upon multivariate analysis. While dose-intensive therapy did not appear to improve outcomes in patients harboring the deletion, the use of radiotherapy was associated with an improved survival.

The investigators present evidence that this mechanism of NF-κB deregulation plays a particularly significant role in the pathobiology of PMBL. Further, they identify NFKBIE deletions as a poor prognostic marker in these patients. Some caution is warranted in generalizing these results, as the functional relevance of the deletion needs to be confirmed in more samples of PMBL. In addition, multiple treatment regimens were used. Recent results have demonstrated potentially superior outcomes with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) in combination with rituximab for patients with PMBL,⁷  results that are being tested in the nearly mature randomized phase 3 trial comparing RCHOP (rituximab, cyclophosphamide, vincristine, and prednisone) with dose-adjusted EPOCH-rituximab in the larger group of diffuse large B-cell lymphomas (NCT00118209).

Nonetheless, the role of NFKBIE in lymphomagenesis and PMBL remains of interest. The ability to tailor therapy for patients with PMBL, such as identifying those most likely to benefit from consolidative radiation, would represent a significant therapeutic advance. Therefore further work is warranted to investigate the predictive ability of this deletion. In addition, this work supports continued efforts to develop novel inhibitors targeting components of the NF-κB pathway.