The EZH2 inhibitor tazemetostat upregulates the expression of CCL17/TARC in B-cell lymphoma and enhances T-cell recruitment.

An inhibitor of the histone methyltransferase enhancer of zeste homologue 2 (EZH2), tazemetostat, has been developed for the treatment of B-cell lymphoma, but its mechanisms of action are not fully elucidated. We screened for genes targeted by tazemetostat in eleven B-cell lymphoma cell lines and found that tazemetostat significantly increased the expression of chemokine (C-C motif) ligand 17 (CCL17)/thymus- and activation-regulated chemokine (TARC) in all, which codes for a chemokine that is a hallmark of Hodgkin/Reed-Sternberg (H/RS) cells in Hodgkin lymphoma. Notably, gene set enrichment analysis demonstrated a positive correlation between the genes upregulated by tazemetostat in five follicular lymphoma (FL) cell lines and those reported to be overexpressed in H/RS cells. The CCL17 promoter region was enriched in repressive histone modification H3K27me3, and tazemetostat induced H3K27 demethylation and activated gene transcription. CCL17 protein secretion was also induced by EZH2 inhibition, which was further enhanced by concurrent CpG stimulation. In vitro transwell migration assay demonstrated that CCL17 produced by tazemetostat-treated B cells enhanced the recruitment of T cells, which had the potential to exert antilymphoma response. Analysis of publicly available human lymphoma databases showed that CCL17 gene expression was inversely correlated with the EZH2 activation signature and significantly paralleled the CD4+ and CD8+ T-cell-rich signature in FL and germinal center B-cell-like diffuse large B-cell lymphoma. Our findings indicate that tazemetostat can potentially activate antilymphoma response by upregulating CCL17 expression in B-cell lymphoma cells and promote T-cell recruitment, which provides a rationale for its combination with immunotherapy.

Establishment and characterization of a MALT lymphoma cell line carrying an API2-MALT1 translocation.

MALT lymphomas with API2(BIRC3)-MALT1 translocation usually have an indolent clinical course and rarely transform into aggressive lymphoma, and there have been no lymphoma cell lines carrying API2-MALT1 translocation reported to date. We established a novel lymphoma cell line named BMA19, carrying the API2-MALT1 translocation from a patient with histologic transformation of intestinal MALT lymphoma. The cells were suggested to carry API2-MALT1 and MYC-IGH translocations by chromosomal analysis, and these translocations were confirmed by polymerase chain reaction analysis. The expression of MYC was shown to be enhanced as a result of the MYC-IGH translocation, and it is considered to have played a role in the histologic transformation of MALT lymphoma. Whole exome sequencing of BMA19 identified several nucleotide variations in genes reported to be mutated in previous studies of marginal zone lymphomas. The MALT1 inhibitor MI-2 specifically decreased cell growth, and the BMA19 cell line was suggested to be still dependent on the API2-MALT1 signal. Subtractive microarray analysis showed that one of the earliest events resulting from MALT1 inhibition is increased susceptibility to endoplasmic reticulum stress-induced apoptosis. The BMA19 cell line is considered to conserve the biological properties of MALT lymphoma and is expected to be a valuable tool for research into the pathogenesis of MALT lymphoma with an API2-MALT1 translocation.

A sporadic case of CTLA4 haploinsufficiency manifesting as Epstein-Barr virus-positive diffuse large B-cell lymphoma.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is a coinhibitory receptor that plays an essential role in maintaining immune system homeostasis by suppressing T-cell activation. We report a sporadic case of CTLA4 haploinsufficiency in a patient with Epstein-Barr virus-positive diffuse large B-cell lymphoma and subsequent benign lymphadenopathy. A missense mutation in exon 2 of the CTLA4 gene (c.251T>C, p.V84A) was found in the patient's peripheral blood and buccal cell DNA, but not in her parents' DNA. CTLA4 expression decreased in the peripheral regulatory T cells upon stimulation, whereas CTLA4 and PD-1-positive T cell subsets increased, possibly to compensate for the defective CTLA4 function. This case suggests that some adult lymphoma patients with no remarkable medical history have primary immune disorder. As immune-targeted therapies are now widely used for the treatment of malignancies, it is increasingly important to recognize the underlying primary immune disorders to properly manage the disease and avoid unexpected complications of immunotherapies.

Surgical treatment of rare giant malignant tumors of the scalp: A report of 3 cases with different tumor types.

The scalp is the most frequent site of occurrence of malignant tumors. As an area that is generally neglected by the patient and not closely monitored during physical examinations, scalp tumors can go unnoticed until they become malignant. The present study reports 3 cases of rare giant malignant tumors of the scalp, namely a peripheral nerve sheath tumor, a fibrous tumor and a malignant proliferating trichilemmal tumor, that were treated at The First Bethune Hospital of Jilin University (Changchun, China). Vascularized free anterolateral thigh flap surgery was performed in 2 of the 3 cases. A local flap repair was applied to the third case. The implanted skin grafts remained viable post-operatively and wound repair was uneventful. No signs of malignancy were detected on the edge of the pathological section upon closer pathological examination. In the follow-up period, no recurrence was detected in any of the cases.

CD43 expression in diffuse large B-cell lymphoma, not otherwise specified: CD43 is a marker of adverse prognosis.

CD43 (leukosialin) is a transmembrane glycoprotein expressed in a variety of hematopoietic cells, including B lymphocytes, and a variety of malignancies including lymphoma, leukemia, and solid tumors. CD43 plays an important role in the development of many diseases, and coexpression of CD43 and CD20 on peripheral B cells is a predictive factor of hematopoietic malignancy. Although CD43 is expressed in approximately 25% of diffuse large B-cell lymphomas (DLBCLs), its prognostic significance remains unclear. To analyze CD43 expression in DLBCL, not otherwise specified (DLBCL, NOS), and assess its prognostic value, we analyzed clinical data from 160 patients with DLBCL, NOS. We observed that CD43 expression was detected in 47 (29.4%) of 160 cases. CD43 expression was positively correlated with old age (>60 years), high serum lactate dehydrogenase level, B symptoms, non-germinal center type, and DLBCL, NOS, mortality. Patients with CD43-positive DLBCL, NOS, had poorer overall survival (P < .001, log-rank test) and event-free survival (P < .001, log-rank test) than CD43-negative patients. Univariate analysis showed that CD43 expression, age, sex, Ann Arbor stage, International Prognostic Index category, and germinal center phenotype were prognostic factors for DLBCL, NOS, patient survival. Multivariate analysis showed that CD43 expression was an independent significant prognostic factor for event-free survival (P < .001) and overall survival (P < .001). Based on these data, we conclude that CD43 expression is a novel adverse prognostic factor for patients with DLBCL, NOS.