Anti-IGHM monoclonal antibody

Epithelioid angiomyolipoma (eAMLoma) is an uncommon renal mesenchymal tumor with malignant potential and is frequently associated with tuberous sclerosis (TSC). It is composed of polygonal large-sized tumor cells arranged in an epithelioid manner. Differential diagnosis from renal cell carcinoma (RCC) is often challenging because of its epithelioid morphology. Herein is reported three cases of eAMLoma, involving one in a 28-year-old man with TSC and two in women without TSC (34 and 62 years of age, respectively). The male TSC patient had microscopic conventional AMLomas in the same kidney. All patients were positive for melanoma (reactive with HMB45 antibody, and positive for melan A, tyrosinase and microphthalmia transcription factor) and smooth muscle markers (positive for alpha-smooth muscle-specific actin), but not for epithelial markers (cytokeratin, epithelial membrane antigen). In particular, the translocation RCC is an important differential diagnostic candidate, in terms of the positive reaction with HMB45 and morphological similarity. The present tumor samples did not show any reactivity for transcription factor binding to IGHM enhancer 3 or transcription factor EB, which excluded the possibility of translocation RCC. The possibility of eAMLoma should be evaluated as a diagnostic candidate, especially in cases of renal tumors (i) in young patients; (ii) associated with TSC; or (iii) with an epithelioid morphology and a high nuclear grade.

The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin mu (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysis-targeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.