EZH2 Mutations Are Related to Low Blast Percentage in Bone Marrow and -7/del(7q) in De Novo Acute Myeloid Leukemia

<div><p>The purpose of the present work was to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo acute myelogenous leukemia by sequencing the entire coding region. EZH2 mutations were identified in 13/714 (1.8%) of AML patients were found to be more common in males (<i>P</i> = 0.033). The presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (<i>P</i><0.0001) and -7/del(7q) (<i>P</i> = 0.025). There were no differences in the incidence of mutation in 13 genes, ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. No difference in complete remission, event-free survival, or overall survival was observed between patients with and without EZH2 mutation (<i>P</i>>0.05). Overall, these results showed EZH2 mutation in de novo acute myeloid leukemia as a recurrent genetic abnormality to be associated with lower blast percentage in BM and -7/del(7q).</p></div

Kaplan-Meier survival curves according to EZH2 mutation status.

<p>(A) EFS in de novo AML patients according to EZH2 mutations. The green line represents patients with mutated EZH2 (n = 12); and magenta line, patients with unmutated EZH2 (n = 277; <i>P</i> = 0.2283); (B) OS in de novo AML patients according to EZH2 mutations. The green line represents patients with mutated EZH2 (n = 12); and the magenta line represents patients with unmutated EZH2 (n = 277; P = 0.5001).</p

Comparison of clinical and laboratory features between AML patients with and without EZH2 mutation.

ψ<p>Risk status: Better-risk: inv(16)/t(16;16), t(8;21),t(15;17); Intermediate-risk: normal, +8, t(9;11), other undefined risk; Poor-risk: complex, −5, 5q−, −7, 7q−, 11q23(non t(9;11)), inv(3), t(3;3), t(6;9), t(9;22).</p><p>(A) Structure of the EZH2 protein and location of EZH2 mutations. (B) DNA sequencing chromatograms of AML genomic DNA samples showing 14 mutations in 13 AML patients.</p

Anion-Mediated Allosteric Catalysis of [2 + 2] Photocycloaddition Based on a Flexible Metallo-Amine Cage for High Diastereoselectivity

Anions can exert a notable influence on the solubility and folding of protein structures, consequently altering their activity and stability due to the well-known Hofmeister effect. Herein, we report a protein-like allosteric metal–organic cage (MOC-68) with the solubility and conformation regulated through anion exchange, leading to conversion between the relaxed state (R-state) and the tensed state (T-state) to show distinct host–guest interactions. This conformational change enables allosteric catalysis of intermolecular [2 + 2] photocycloaddition of acyclic olefins with greatly enhanced yield and diastereoselectivity. Kinetic experiments reveal that the T-state of MOC-68 is superior in catalytic performance for the steric and thermodynamic unfavored syn-HH product, displaying a threefold rate enhancement over the R-state and totally a sevenfold increase owing to the reaction acceleration contributed by an enzymatic cage effect. Notably, this allosteric cage exhibits exceptional stability and recyclability, maintaining consistent catalytic efficiency and selectivity over five cycles. This work highlights the potential of structural allostery in flexible cages to enhance the substrate-binding ability and catalytic selectivity, providing a way to advance enzyme-mimicking cage catalysis to regulatable and efficient allosteric catalysis

Anion-Mediated Allosteric Catalysis of [2 + 2] Photocycloaddition Based on a Flexible Metallo-Amine Cage for High Diastereoselectivity

Anions can exert a notable influence on the solubility and folding of protein structures, consequently altering their activity and stability due to the well-known Hofmeister effect. Herein, we report a protein-like allosteric metal–organic cage (MOC-68) with the solubility and conformation regulated through anion exchange, leading to conversion between the relaxed state (R-state) and the tensed state (T-state) to show distinct host–guest interactions. This conformational change enables allosteric catalysis of intermolecular [2 + 2] photocycloaddition of acyclic olefins with greatly enhanced yield and diastereoselectivity. Kinetic experiments reveal that the T-state of MOC-68 is superior in catalytic performance for the steric and thermodynamic unfavored syn-HH product, displaying a threefold rate enhancement over the R-state and totally a sevenfold increase owing to the reaction acceleration contributed by an enzymatic cage effect. Notably, this allosteric cage exhibits exceptional stability and recyclability, maintaining consistent catalytic efficiency and selectivity over five cycles. This work highlights the potential of structural allostery in flexible cages to enhance the substrate-binding ability and catalytic selectivity, providing a way to advance enzyme-mimicking cage catalysis to regulatable and efficient allosteric catalysis

Additional file 2: Table S2. of Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients

Treatment response at the four different dose levels (DLs). DL1: Azacitidine (AZA) 55 mg/m2 days 1–5 and vorinostat (VST) 300 mg BID days 1–7. DL2: AZA 75 mg/m2 days 1–5 and VST 200 mg BID days 1–7. DL3: AZA 55 mg/m2 days 1–5 and VST 300 mg BID days 1–14. DL4: AZA 75 mg/m2 days 1–5 and VST 200 mg BID days 1–14. (DOC 39 kb

Additional file 1: Table S1. of Combinatorial epigenetic therapy in diffuse large B cell lymphoma pre-clinical models and patients

Toxicity. Highest grade of treatment-emergent adverse events encountered at the four different dose levels. (DLs). DL1: azacitidine (AZA) 55 mg/m2 days 1–5 and vorinostat (VST) 300 mg BID days 1–7. DL2: AZA 75 mg/m2 days 1–5 and VST 200 mg BID days 1–7. DL3: AZA 55 mg/m2 days 1–5 and VST 300 mg BID days 1–14. DL4: AZA 75 mg/m2 days 1–5 and VST 200 mg BID days 1–14. (DOC 57.0 kb