EZH2 Knockout Cell Lysate

We validated the use of somatic mutations to determine acute myeloid leukemia (AML) ontogeny in elderly patients. We identified 178 elderly (> 70 years) patients with AML who were divided clinically into primary (n = 95) or secondary (sAML) (n = 82) AML based on prior history of antecedent hematologic disease. Patients were then reclassified into 4 groups based on somatic mutations and cytogenetics as suggested by Lindsley et al. Based on the AML ontogeny proposed, 8 patients were classified as primary AML, 72 patients as sAML, 28 patients had TP53 mutation, and 70 patients were classified as non-otherwise specified. The median overall survival was 22.4, 14, 2.8, and 11.2 months, respectively; 44% of patients (n = 32) classified molecularly as sAML had no prior antecedent hematologic disease. Our data shows that molecular annotation of elderly patients with AML reclassifies a significant proportion of patients as sAML, which may have therapeutic implications. Background: Acute myeloid leukemia (AML) in elderly patients is associated with poor outcomes and often arises from antecedent hematologic disorders (AHD), classified as secondary AML (sAML). Patients and Methods: To validate the use of somatic mutations to determine AML ontogeny in the elderly population, we identified 178 elderly (> 70 years) patients with AML with NexGen Sequencing data. Patients were divided clinically into primary AML (pAML) or sAML based on prior history of AHD. Patients were then reclassified into 4 groups based on somatic mutations and cytogenetics as suggested by Lindsley et al: group 1 (pAML) with CBF rearrangements, 11q23/MLL, and NPM1 mutation (MT); group 2 (sAML) with SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 MT; group 3 with TP53 MT; and group 4 as not otherwise specified (NOS). Results: Based on clinical criteria, 95 patients were classified as pAML and 82 patients as sAML. Based on the AML ontogeny proposed, 8 patients were classified as pAML, 72 patients as sAML, 28 patients had TP53 MT, and 70 patients were classified as NOS. The median overall survival was 22.4,14, 2.8, and 11.2 months, respectively. Clinical versus molecular classification was discordant where 25% (n = 2) of patients classified as pAML by molecular signature had a history of AHD, whereas 44% (n = 32) of patients classified molecularly as sAML had no prior AHD. In the TP53 MT and NOS categories, 37% (n = 28) and 43% (n = 70) of patients had AHD, respectively. Conclusion: Our data shows that molecular annotation of elderly patients with AML reclassifies a significant proportion of patients as sAML, which may have therapeutic implications.

Endometriosis is a painful gynecological disease with no cure and limited therapeutic options. It has been hypothesized that epigenetic drugs can be used as a nonhormonal treatment for endometriosis. This study was conducted to study the efficacy of an inhibitor of the histone methyltransferase EZH2 using an established rat model of endometriosis. We hypothesized that treatment will block or reduce the number of endometriotic vesicles in this model. We conducted a preclinical drug study in female rats with experimental endometriosis (uterine tissue transplanted next to the intestinal mesentery) or control sham (sutures only). Rats with endometriosis or sham surgery received either treatment with EZH2 inhibitor (5 mg/kg or 10 mg/kg) or vehicle (0.1%, 67% DMSO) every other day during 4 weeks. After treatment completion, the number, area, volume, and weight of vesicles were evaluated. RT [2] Profiler Arrays for neuropathic and inflammation, epithelial to mesenchymal transition, inflammatory response, and autoimmunity pathways were used to examine gene expression changes in the vesicles that developed. Treatment with EZH2 inhibitor (10 mg/kg) suppressed the development of vesicles, by significantly decreasing the total vesicle number, area, volume, and weight. In addition, EZH2 inhibition significantly increased the expression ofCACNA1BandFKBP1Agenes, involved in pain and proliferation, respectively. EZH2 inhibition suppresses the growth of vesicles without apparent detrimental effects to other organs. Treatment with this epigenetic inhibitor leads to upregulation of a limited number of genes related to endometriosis-relevant pathways. In conclusion, these data support follow-up studies to evaluate its potential as a therapeutic approach for endometriosis.