The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.

SUMMARY The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia that is mainly diagnosed in children and shows a skewed gender distribution toward males. In this study, we report somatic loss-of-function mutations in the X-linked histone H3K27me3 demethylase ubiquitously transcribed X (UTX) chromosome, in human T-ALL. Interestingly, UTX mutations were exclusively present in male T-ALL patients and allelic expression analysis revealed that UTX escapes X-inactivation in female T-ALL lymphoblasts and normal T cells. Notably, we demonstrate in vitro and in vivo that the H3K27me3 demethylase UTX functions as a bona fide tumor suppressor in T-ALL. Moreover, T-ALL driven by UTX inactivation exhibits collateral sensitivity to pharmacologic H3K27me3 inhibition. All together, our results show how a gender-specific and therapeutically relevant defect in balancing H3K27 methylation contributes to T-cell leukemogenesis

Background Transaxillary thyroidectomy (TAT) has gained popularity in East Asian countries; however, to date there have been no attempts to evaluate the preferences regarding TAT in the United States population. The aim of this study is to assess the preferences and considerations associated with TAT in an American cohort. Methods Self-administered surveys were distributed to 966 adults at various locations in a single state. Questions assessed preferences for the surgical approach, acceptable risks and extra costs, and willingness to pursue TAT despite reduced cancer treatment efficacy. Results The response rate was 84% with a mean age of 40±17 years. The majority of respondents were female. Eighty-two percent of the respondents preferred TAT to a cervical thyroidectomy (CerT), all risks being equal. Fifty-one percent of the respondents were willing to accept a 4% complication rate with TAT. Sixteen percent of the respondents stated they would agree to pay up to an additional $5,000 for the TAT approach. When presented with thyroid cancer, 20% of all respondents still preferred TAT even if it would not cure their disease. Patients preferring TAT over CerT were younger, female, more willing to accept complications and spend additional money, and most significantly, preferred the TAT approach even if it was less likely to cure their cancer. Conclusions Although this survey presents a hypothetical question for people who do not have thyroid disease, the majority of respondents preferred TAT over CerT. Furthermore, a substantial number were willing to accept higher complication rates and increased costs for TAT.

Potentiostatic measurements of the three principle faces of oriented single Pt crystals and polycrystalline Pt showed some interesting comparisons. True areas are based on Pt atom densities, and under the electrochemical treatment used, no changes in these areas were found once the initial surface cleaning was completed. The hydrogen overvoltage was independent of crystal orientation or other metallurgical factors; however, the passivation of the hydrogen oxidation reaction and the oxygen generation reactions were different for each single crystal orientation with a large difference between these faces and a polycrystalline bead electrode. Steady‐state relations between potential and amounts of associated H atoms and number of sites available for coverage with O atoms were determined also. These steady‐state values are generally less than the comparative amounts found under transient conditions. Oxygen evolution on the Pt faces was not observed below a potential of 1.8V. It appears that grain boundaries, stress, and impurity inclusions may have more effect in determining the catalytic activity for some reactions than does the actual atomic density or geometry of Pt atoms.