Rebecca L. Boddicker

The oncogenic transcription factor IRF4 is regulated by a novel CD30/NF-κB positive feedback loop in peripheral T-cell lymphoma

Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Because direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified nuclear factor κB (NF-κB) as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB subunits p52 and RelB were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs.

DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study

To the editor: Peripheral T-cell lymphomas (PTCLs) represent a group of rare hematological cancers of mature T-cell or natural killer cell origin accounting for 10% to 15% of all lymphomas.[1][1] Although many patients have poor outcomes, some achieve long-term survival.[2][2],[3][3] Thus,

Expression of p63 protein in anaplastic large cell lymphoma: implications for genetic subtyping

Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas that bear chromosomal rearrangements of the TP53 homologue TP63 in a subset of cases that demonstrate aggressive clinical behavior. In the present study, we examined the relationship between p63 protein expression by immunohistochemistry and the results of fluorescence in situ hybridization using TP63 probes in 116 ALCLs. We also determined the relative expression of full-length TAp63 and truncated ΔNp63 isoforms (eg, p40) in ALCL cell lines and a subset of clinical cases. Overall, 35.3% of ALCLs were positive for p63 protein. Primary cutaneous and anaplastic lymphoma kinase-negative ALCLs were positive more frequently than anaplastic lymphoma kinase-positive ALCLs (P=.0034). As previously reported, cases with TP63 gene rearrangements expressed p63 uniformly. p63 expression in nonrearranged cases was associated with extra copies of TP63 on 3q28 (P<.0001). Extra copies of TP63 correlated with extra copies of the DUSP22 locus on 6p25.3 (P<.0001). Results of immunohistochemistry, Western blotting, and RNA sequencing indicated that p63 expression in nonrearranged cases was entirely attributable to TAp63 isoforms. Taken together, these findings indicate that ALCLs without TP63 rearrangements may express TAp63 isoforms of p63 and that this expression is associated with extra copies of TP63, probably due to widespread genomic copy number abnormalities rather than focal gains. Immunohistochemistry for p63 in ALCL is not specific for TP63 rearrangements but is useful clinically as a screening test to select cases for further testing by fluorescence in situ hybridization. Immunohistochemistry for ΔNp63 (p40) is not informative in the evaluation of ALCL.

Genetic Landscape and Classification of Peripheral T Cell Lymphomas

Purpose of reviewPeripheral T cell lymphomas (PTCLs) are markedly heterogeneous at the clinical, pathological, and molecular levels. This review will discuss genetic findings in PTCL with special emphasis on how they impact lymphoma classification.Recent findingsSequencing studies have identified recurrent genetic alterations in nearly every PTCL subtype. In anaplastic large cell lymphoma, these studies have revealed novel chromosomal rearrangements and mutations that have prognostic significance and may suggest new therapeutic approaches. Angioimmunoblastic T cell lymphoma has been found to have mutations overlapping some cases of PTCL, not otherwise specified with a T follicular helper cell phenotype. Across various subtypes, recurrent mutations and structural alterations affecting genes involved in epigenetic regulation, T cell receptor signaling, and immune response may represent targets for precision therapy approaches.SummaryNew genetic findings are refining the classification of PTCLs and are beginning to be used clinically for diagnosis, risk stratification, and individualized therapy.

Progress in the identification of subgroups in ALK-negative anaplastic large-cell lymphoma

Classification of anaplastic large cell lymphoma: historical background Anaplastic large cell lymphoma (ALCL) represents a group of non-Hodgkin lymphomas of mature T-cell origin (peripheral T-cell lymphomas [PTCLs]) that share common pathologic features, especially the presence of large lymphocytes that often involve lymph node sinuses and express the Ki-1 antigen, now designated CD30 [1]. A chromosomal rearrangement in a subset of these cases, t(2;5)(p23;q35), was found to involve the nucleophosmin gene, NPM1, and a novel tyrosine kinase gene, designated anaplastic lymphoma kinase or ALK [2]. Immunohistochemical staining for ALK allowed recognition that cases with several histologic patterns as well as cases with variant, nonNPM1 partner genes could be unified into a common clinicopathologic entity, ALK-positive ALCL [3]. An additional group of cases lacked ALK rearrangements, and these ALKnegative ALCLs occurred in older patients and had inferior outcomes compared with ALK-positive ALCLs [4]. The fourth edition of the WHO classification of lymphomas provisionally classified ALK-negative ALCL as a distinct entity separate from ALK-positive ALCL [5], and this provisional status is likely to be dropped in a forthcoming WHO update. Nevertheless, diagnostic criteria for ALK-negative ALCL still are evolving, particularly to distinguish it from other CD30positive PTCLs [5–7]. Primary cutaneous ALCL is recognized separately by the WHO and represents ALCLs that present in the skin and typically have excellent long-term outcomes [5]; these tumors share some genetic features with systemic ALCLs, as discussed below. The pathogenic role of ALK fusions in ALK-positive ALCL has been studied extensively; however, the pathobiology of ALKnegative ALCL remains incompletely understood [6]. Gene expression profiling studies have identified a molecular signature for ALK-positive ALCL and another signature common to all ALCLs [7]. This latter signature can help distinguish ALCL from other PTCLs, but identifying a signature specific for ALK-negative ALCL has proved challenging. This difficulty likely relates in part to intrinsic molecular heterogeneity within the category of ALK-negative ALCL.

Targetable fusions of the FRK tyrosine kinase in ALK-negative anaplastic large cell lymphoma

Targetable fusions of the FRK tyrosine kinase in ALK-negative anaplastic large cell lymphoma

Recurrent stat3-jak2 fusions in indolent t-cell lymphoproliferative disorder of the gastrointestinal tract

TO THE EDITOR: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (GI TLPD) is a newly recognized entity in the World Health Organization (WHO) classification of lymphoid neoplasms.[1][1] GI TLPD is defined as a clonal T-cell proliferation occurring in the GI tract, most

Genetic subtyping of breast implant–associated anaplastic large cell lymphoma

TO THE EDITOR: Anaplastic large cell lymphomas (ALCLs) represent a group of CD30-positive T-cell non-Hodgkin lymphomas with unifying morphological characteristics but variable clinical and genetic features. ALCLs are classified by their clinical presentation and the presence or absence of

Genetic alterations affecting GTPases and T-cell receptor signaling in peripheral T-cell lymphomas.

ABSTRACT Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous tumors with poor response to standard therapy and few targeted treatments available. The identification of mutations in the T-cell receptor (TCR) signaling pathway that either directly or indirectly affect Ras- and Rho-family GTPases is an emerging theme across PTCL subtypes. This review summarizes the role of GTPases in TCR signaling and highlights the constellation of mutations in this pathway among PTCLs. In particular, focus is given to the functional impact of the mutations and opportunities for targeted therapy. These mutations include activating mutations and gene fusions involving the guanine nucleotide exchange factor, VAV1, as well as activating and dominant negative mutations in the GTPases KRAS and RHOA, respectively. In addition to mutations directly affecting the GTPase pathway, TCR signaling mutations indirectly affecting Ras- and Rho-family GTPases involving genes such as CD28, FYN, LCK, and PLCG1 are also reviewed.

Anaplastic large cell lymphoma, ALK-negative

Review on Anaplastic large cell lymphoma, ALKnegative, with data on clinics, and the genes involved.