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Chromosome translocations involving the MLL gene are common rearrangements in leukemia. Such translocations fuse the MLL 5’-region to partner genes in frame, producing MLL-fusions that cause MLL-related leukemia. MLL-fusions activate transcription of target genes such as HoxA cluster and Meis1 , but the underlying mechanisms remain to be fully elucidated. In this study, we discovered that Tip60, a MYST-type histone acetyltransferase, was required for the expression of HoxA cluster and Meis1 genes and the development of MLL-fusion leukemia. Tip60 was recruited by MLL-AF10 and MLL-ENL fusions to the Hoxa9 locus, where it acetylated H2A.Z, thereby promoting Hoxa9 gene expression. Conditional deletion of Tip60 prevented the development of MLL-AF10 and MLL-ENL leukemia, indicating that Tip60 is indispensable for the leukemogenic activity of the MLL-AF10 and MLL-ENL-fusions. Our findings provide novel insight about epigenetic regulation in the development of MLL-AF10 and MLL-ENL-fusion leukemia.

Mantle cell lymphoma (MCL) is a rare subtype of non‐Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR‐S1 (a close analog of the clinical‐stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib‐resistant MCL patient–derived xenograft (PDX) mouse model, OR‐S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2‐specific inhibitor GSK126, OR‐S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR‐S1–sensitive or insensitive MCL cell lines and showed that OR‐S1 treatment modulated B‐cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for the treatment of aggressive ibrutinib‐resistant MCL via CDKN1C‐mediated cell cycle arrest. This study reveals that oral administration of OR‐S1 significantly suppressed tumor growth in an ibrutinib‐resistant mantle cell lymphoma (MCL) patient–derived xenograft mouse model. OR‐S1 induces cell cycle arrest via the upregulation of CDKN1C. CDKN1C expression was directly regulated by enhancer of zeste homologs 1 and 2 (EZH1/2).

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.

Multiple myeloma (MM) is an incurable hematological malignancy caused by accumulation of abnormal clonal plasma cells. Despite the recent development of novel therapies, relapse of MM eventually occurs as a result of a remaining population of drug‐resistant myeloma stem cells. Side population (SP) cells show cancer stem cell‐like characteristics in MM; thus, targeting these cells is a promising strategy to completely cure this malignancy. Herein, we showed that SP cells expressed higher levels of enhancer of zeste homolog (EZH) 1 and EZH2, which encode the catalytic subunits of Polycomb repressive complex 2 (PRC2), than non‐SP cells, suggesting that EZH1 as well as EZH2 contributes to the stemness maintenance of the MM cells and that targeting both EZH1/2 is potentially a significant therapeutic approach for eradicating myeloma stem cells. A novel orally bioavailable EZH1/2 dual inhibitor, OR‐S1, effectively eradicated SP cells and had a greater antitumor effect than a selective EZH2 inhibitor in vitro and in vivo, including a unique patient‐derived xenograft model. Moreover, long‐term continuous dosing of OR‐S1 completely cured mice bearing orthotopic xenografts. Additionally, PRC2 directly regulated WNT signaling in MM, and overactivation of this signaling induced by dual inhibition of EZH1/2 eradicated myeloma stem cells and negatively affected tumorigenesis, suggesting that repression of WNT signaling by PRC2 plays an important role in stemness maintenance of MM cells. Our results show the role of EZH1/2 in the maintenance of myeloma stem cells and provide a preclinical rationale for therapeutic application of OR‐S1, leading to significant advances in the treatment of MM. Long‐term continuous administration of OR‐S1 completely cured all mice bearing orthotopic xenografts without eliciting any serious side‐effects. We confirmed this result by counting minimal residual cells by flow cytometric analysis. These results suggest that long‐term continuous administration of OR‐S1 impairs the self‐renewal activity of myeloma stem cells, rendering these cells unable to reconstitute disease and leading to the complete cure of MM.

The chromatin-associated AAA+ ATPases Tip48 and Tip49 are the core components of various complexes implicated in diverse nuclear events such as DNA repair and gene regulation. Although they are frequently overexpressed in many human cancers, their functional significance remains unclear. Here, we show that loss of Tip49 triggered p53-dependent apoptosis and inhibited leukemia development in vivo. To examine the impact of chemical inhibition of this complex on leukemia, we have developed the novel compound DS-4950, which interferes with the ATPase activity of the Tip48/49. Administration of DS-4950 was well-tolerated in healthy mice, and the drug effectively reduced tumor burden and improved survival. We also provide evidence that the dependency on Tip48/49 is widely conserved in non-hematologic malignancies with wild type p53. These results demonstrated that the Tip48/49 ATPases are functionally necessary and therapeutically targetable for the treatment of human cancers.

In verapamil-sensitive left posterior fascicular ventricular tachycardia (LPF-VT), radiofrequency catheter ablation (RFA) is performed targeting mid-to-late diastolic potential (P1) and presystolic potential (P2) during tachycardia. This study included four patients who had undergone electrophysiological study (EPS) and pediatric patients with verapamil-sensitive LPF-VT who had undergone RFA using high-density three-dimensional (3D) mapping. The included patients were 11–14 years old. During EPS, right bundle branch block and superior configuration VT were induced in all patients. VT mapping was performed via the transseptal approach. P1 and P2 during VT were recorded in three of the four patients. All patients initially underwent RFA via the transseptal approach. In three patients, P1 during VT was targeted, and VT was terminated. The lesion size indices in which VT was terminated were 4.6, 4.6, and 4.7. For one patient whose P1 could not be recorded, linear ablation was performed perpendicularly in the area where P2 was recorded during VT. Among the three patients in whom VT was terminated, linear ablation was performed in two to eliminate the ventricular echo beats. In all patients, VT became uninducible in the acute phase and had not recurred 8–24 months after RFA. High-density 3D mapping with an HD Grid Mapping Catheter allows recording of P1 and P2 during VT and may improve the success rate of RFA in pediatric patients with verapamil-sensitive LPF-VT.

Background In patients with chronic obstructive pulmonary disease (COPD), the maximum level of diaphragm excursion (DE max ) is correlated with dynamic lung hyperinflation and exercise tolerance. This study aimed to elucidate the utility of DE max to predict the improvement in exercise tolerance after pulmonary rehabilitation (PR) in patients with COPD. Methods This was a prospective cohort study. Of the 62 patients with stable COPD who participated in the outpatient PR programme from April 2018 to February 2021, 50 completed the programme. Six-minute walk distance (6MWD) was performed to evaluate exercise tolerance, and ultrasonography was performed to measure DE max . Responders to PR in exercise capacity were defined as patients who demonstrated an increase of > 30 m in 6MWD. The receiver operating characteristic (ROC) curve was used to determine the cut-off point of DE max to predict responses to PR. Results Baseline levels of forced expiratory volume in 1 s, 6MWD, maximum inspiratory pressure, DE max and quadriceps muscle strength were significantly higher, and peak dyspnoea of modified Borg (mBorg) scale score was lower in responders (n = 30) than in non-responders (n = 20) to PR (p < 0.01). In multivariate analysis, DE max was significantly correlated with an increase of > 30 m in 6MWD. The area under the ROC curve of DE max to predict responders was 0.915, with a sensitivity and specificity of 83% and 95%, respectively, at a cut-off value of 44.9 mm of DE max . Conclusion DE max could adequately predict the improvement in exercise tolerance after PR in patients with COPD.

We encountered a case of a one-year-old girl who was diagnosed with focal atrial tachycardia (FAT) at two months old. The FAT was controlled with medical treatment. However, she later developed pallor and tachycardia, with a heart rate of 180 beats per minute (bpm). This occurred after an acute onset of high-grade fever for four days, followed by rapid fever reduction and a rash. She exhibited signs of chest discomfort by grabbing her clothes around her chest and complaining of chest pain. On the second day after the fever subsided, she suddenly became pale with tachycardia and was brought to our emergency department. A 12-lead electrocardiogram (ECG) revealed a sinus rhythm of approximately 120 bpm with frequent nonsustained FAT. Initial laboratory investigations showed normal results: creatinine kinase at 99 IU/L, troponin T at 0.010 ng/mL, and an elevated B-type natriuretic peptide level at 95.1 pg/mL. Echocardiography revealed a pericardial effusion of up to 6.6 mm despite normal cardiac function. We clinically diagnosed her with acute pericarditis and administered aspirin. The pericardial effusion resolved after two weeks but recurred two months later. Prednisolone was administered for recurrent pericarditis, and aspirin was replaced with colchicine. After one month, the pericardial effusion was resolved, and the prednisolone was discontinued. Subsequent echocardiography showed no pericardial effusion and no evidence of diastolic dysfunction. The quantitative polymerase chain reaction confirmed the presence of human herpesvirus 6 (HHV-6) in her serum at the onset of the disease. Additionally, serologic tests conducted in acute and chronic phases indicated viral antibody titers that were eight and 256 times higher, respectively. In conclusion, the HHV-6 virus can cause acute viral pericarditis in patients with exanthema subitum.

Ablation index (AI)-guided ablation is useful for pulmonary vein isolation (PVI) and cavotricuspid isthmus (CTI) ablation. However, the impact of radiofrequency (RF) application power on CTI ablation with a fixed target AI remains unclear. One-hundred-thirty drug-refractory atrial fibrillation and/or atrial flutter patients who underwent AI-guided CTI ablation with or without PVI between July 2020 and August 2021 were randomly assigned to high-power (45 W) and moderate-power (35 W) groups. We performed CTI ablation with the same target AI value in both groups: 500 for the anterior 1/3 segments and 450 for the posterior 2/3 segments. In total, first-pass conduction block of the CTI was obtained in 111 patients (85.4%), with 7 patients (5.4%) showing CTI reconnection. The rate of first-pass conduction block was significantly higher in the 45 W group (61/65, 93.8%) than in the 35 W group (50/65, 76.9%, P = 0.01). CTI ablation and CTI fluoroscopy time were significantly shorter in the 45 W group than in the 35 W group (CTI ablation time: 192.3 ± 84.8 vs. 319.8 ± 171.4 s, P < 0.0001; CTI fluoroscopy time: 125.2 ± 122.4 vs. 171.2 ± 124.0 s, P = 0.039). Although there was no significant difference, steam pops were identified in two patients from the 45 W group at the anterior segment of the CTI. The 45 W ablation strategy was faster and provided a higher probability of first-pass conduction block than the 35 W ablation strategy for CTI ablation with a fixed AI target.

Left pulmonary artery stenosis is a well-recognized complication following the Norwood procedure. We herein report two cases in which ascending aortic extension was performed to enlarge the retroaortic space in children with left pulmonary artery stenosis after the Norwood procedure. We used graft interposition in the ascending aorta to increase the retroaortic apace and concomitantly performed extended left pulmonary artery reconstruction. This procedure obtains a more balanced distribution of the pulmonary blood flow, which is crucial to achieve good Fontan circulation.