YM155 induces apoptosis through proteasome-dependent degradation of MCL-1 in primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a lymphoma that shows malignant effusion in body cavities without contiguous tumor masses and has a very poor prognosis. We recently developed a novel drug screening system using patient-derived xenograft (PDX) cells that maintained the primary cell phenotype better than cell lines. This screening is expected to discover anti-tumor drugs that have been overlooked by conventional screening using cell lines. We herein performed this screening to identify new therapeutic agents for PEL. We screened 3518 compounds with known pharmaceutical activities based on cytotoxic effects on PDX cells of PEL and selected YM155, a possible survivin inhibitor. It exerted strong anti-tumor effects in PDX cells and three cell lines of PEL; the GI50 of YM155 was 1.2-7.9nM. We found that YM155 reduced myeloid cell leukemia-1 (MCL-1) protein levels prior to decreasing survivin levels, and this was inhibited by a proteasome inhibitor. The knockdown of MCL-1 by siRNA induced cell death in a PEL cell line, suggesting the involvement of decreased MCL-1 levels in YM155-induced cell death. YM155 also induced the phosphorylation of ERK1/2 and MCL-1, and a MEK1 inhibitor inhibited the phosphorylation of ERK1/2, degradation of MCL-1, and YM155-induced apoptosis. These results indicate that YM155 induces the proteasome-dependent degradation of MCL-1 through its phosphorylation by ERK1/2 and causes apoptosis in PEL cells. Furthermore, a treatment with YM155 significantly inhibited the development of ascites in PEL PDX mice. These results suggest the potential of YM155 as an anti-cancer agent for PEL.

[Morphological changes in meibomian glands following radiotherapy].

PURPOSE: To examine the morphological changes in meibomian glands using noncontact infrared meibography in patients undergoing radiotherapy and to compare the results with those of a normal population. CASES AND METHOD: Thirteen eyes of 8 patients (2 men and 6 women; 65.1 +/- 17.6 years, mean +/- standard deviation) diagnosed as having ocular adnexal lymphoma and had undergone radiotherapy were included in this study. Meibomian gland morphological changes (meiboscore) were assessed by noncontact meibography. The results were compared with those of forty-one eyes of 21 healthy volunteers (9 men and 12 women ; 66.9 +/- 11.6 years). RESULTS: The meiboscore was 3.69 +/- 0.75 in the irradiation group and 2.41 +/- 1.34 in the control group, showing a significant difference between the groups (p = 0.0029). When compared with the irradiated and fellow eyes in the patients with unilateral radiotherapy, the mean meiboscore of irradiated eyes (4.00 +/- 1.00) was higher than that of the fellow eyes (2.66 +/- 0.57) even though there was no significant difference. CONCLUSION: Radiotherapy causes morphological changes in the meibomian glands such as atrophy and dropout.

ZNF384-fusion proteins have high affinity for the transcriptional coactivator EP300 and aberrant transcriptional activities.

Zinc-finger protein 384 (ZNF384) fusion (Z-fusion) genes have recently been identified as recurrent fusion genes in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) and have been detected in 7-17% of Philadelphia chromosome-negative BCP-ALL cases. We selected SALL4 and ID2 as potential Z-fusion-specific transcriptional targets that might lead to the differentiation disorder of Z-fusion-positive ALL. The introduction of EP300-ZNF384 and SYNRG-ZNF384 induced the expression of these genes. Z-fusion proteins exhibited stronger transcriptional activities on the promoter or enhancer region of these genes than Wild-Z. Furthermore, GST pull-down assay revealed that Z-fusion proteins associated more strongly with EP300 than Wild-Z. Coexpression of EP300 specifically enhanced the transcriptional activities of Z-fusion proteins. We propose the increased EP300 binding of Z-fusion proteins as a mechanism for their increased transcriptional activities.