IntroductionSystemic anaplastic large-cell lymphomas (ALCLs) are a peripheral T cell-derived malignancy accounting for approximately 12% of all T-cell non-Hodgkin lymphomas (T-NHLs). 1 Originally described by Stein et al in 1985 as ALCL-expressing CD30, 2 its definition and relationship with other T-NHLs has undergone a series of revisions. 1,3,4 Based on genetic and clinical features, 2 different entities are now recognized as systemic forms, the ALK-positive (ALK ϩ ) and ALK-negative (ALK Ϫ ) ALCL. 1,5 The first entity is characterized by recurrent chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene, which leads to the expression and constitutive activation of anaplastic lymphoma kinase (ALK) fusion proteins. 6,7 Whereas ALK ϩ ALCL are readily diagnosed by anti-ALK Abs, the recognition of ALK Ϫ ALCL is in some instances subjective. In fact, immunophenotypic or genetic features that define ALK Ϫ ALCL precisely are missing; accordingly, ALK Ϫ ALCL has been considered a provisional entity by the World Health Organization (WHO) classification. 1 Although all ALCLs display strong and diffuse immunoreactivity for CD30, the expression of this marker is not specific for ALCL. Indeed, CD30 is found also in activated nonneoplastic lymphoid cells, in a subset of peripheral T-cell lymphoma not otherwise specified (PCTL-NOS), in Hodgkin lymphoma, and other neoplasms such as embryonal carcinoma. 8 At present, the diagnosis of ALCL relies on the application of a panel of Abs for B-and T cell-restricted antigens, epithelial membrane antigen (EMA), granzyme B, perforin, and T cell-restricted intracellular antigen-1 (TIA1). 5 ALCLs usually show an aberrant T-cell phenotype with frequent loss of the common T-cell markers such as the pan-T-cell antigens, 9 although in approximately 85%-90% of ALCL clonal TCR gene rearrangement can be detected by PCR. Furthermore, PAX5 negativity is critical for the differentiation of ALCL from common Hodgkin lymphoma and CD30 ϩ diffuse large B-cell lymphoma. 10 Recently, chromosomal translocations affecting 6p25.3, which targets DUSP22 and/or IRF4 have been described in a subset of ALK Ϫ ALCLs, with predominant cutaneous involvement 11,12 ; however, the effects on the pathogenesis of this lymphoma are still largely unknown. ALK Ϫ ALCL distinction is supported by genetic criteria, epidemiologic data, and clinical features. The crude 5-year overall survival of this lymphoma is 49%, a value intermediate between 70% for ALK ϩ ALCL and 32% for PTCL-NOS. 1 Nevertheless, when patients are stratified according to the clinical parameters The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From (ie, age and/or stage), ALK ϩ and ALK Ϫ ALCL patients display a similar prognosis in terms of f...

• Endogenous intronic long terminal repeats promote the ectopic expression of truncated ERBB4 transcripts in 24% of ALK-negative ALCL.• The expression of ERBB4-aberrant transcripts defines a new subclass of ALKnegative ALCL and may contribute to ALCL transformation.Anaplastic large-cell lymphoma (ALCL) is a clinical and biological heterogeneous disease that includes systemic anaplastic lymphoma kinase (ALK)-positive and ALKnegative entities. To discover biomarkers and/or genes involved in ALK-negative ALCL pathogenesis, we applied the cancer outlier profile analysis algorithm to a gene expression profiling data set including 249 cases of T-cell non-Hodgkin lymphoma and normal T cells. Ectopic coexpression of ERBB4 and COL29A1 genes was detected in 24% of ALK-negative ALCL patients. RNA sequencing and 59 RNA ligase-mediated rapid amplification of complementary DNA ends identified 2 novel ERBB4-truncated transcripts displaying intronic transcription start sites. By luciferase assays, we defined that the expression of ERBB4-aberrant transcripts is promoted by endogenous intronic long terminal repeats. ERBB4 expression was confirmed at the protein level by western blot analysis and immunohistochemistry. Lastly, we demonstrated that ERBB4-truncated forms show oncogenic potentials and that ERBB4 pharmacologic inhibition partially controls ALCL cell growth and disease progression in an ERBB4-positive patient-derived tumorgraft model. In conclusion, we identified a new subclass of ALK-negative ALCL characterized by aberrant expression of ERBB4-truncated transcripts carrying intronic 59 untranslated regions. (Blood. 2016;127(2):221-232)

Proteasome inhibitors (PI) are extensively used for the therapy of multiple myeloma (MM) and mantle cell lymphoma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PI, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (IDH2) was identified as a top candidate, showing a synthetic lethal activity with the PI carfilzomib (CFZ). Combinations of US Food and Drug Administration–approved PI with a pharmacological IDH2 inhibitor (AGI-6780) triggered synergistic cytotoxicity in MM, mantle cell lymphoma, and Burkitt lymphoma cell lines. CFZ/AGI-6780 treatment increased death of primary CD138+ cells from MM patients and exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone marrow–derived stromal cells. Mechanistically, the CFZ/AGI-6780 combination significantly decreased tricarboxylic acid cycle activity and adenosine triphosphate levels as a consequence of enhanced IDH2 enzymatic inhibition. Specifically, CFZ treatment reduced the expression of nicotinamide phosphoribosyltransferase (NAMPT), thus limiting IDH2 activation through the NAD+-dependent deacetylase SIRT3. Consistently, combination of CFZ with either NAMPT or SIRT3 inhibitors impaired IDH2 activity and increased MM cell death. Finally, inducible IDH2 knockdown enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PI, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PI to other malignancies.

Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO2. The discovery of IDH1 and IDH2 mutations in several malignancies has brought to the approval of drugs targeting IDH1/2 mutants in cancers. Here, we summarized findings addressing the impact of IDH mutants in rare pathologies and focused on the relevance of non-mutated IDH enzymes in tumors. Several pieces of evidence suggest that the enzymatic inhibition of IDHs may have therapeutic potentials also in wild-type IDH cancers. Moreover, IDHs inhibition could enhance the efficacy of canonical cancer therapies, such as chemotherapy, target therapy, and radiotherapy. However, further studies are required to elucidate whether IDH proteins are diagnostic/prognostic markers, instrumental for tumor initiation and maintenance, and could be exploited as targets for anticancer therapy. The development of wild-type IDH inhibitors is expected to improve our understanding of a potential non-oncogenic addition to IDH1/2 activities and to fully address their applicability in combination with other therapies.

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