A zinc-finger protein Moc3 functions as a transcription activator to promote RNAi-dependent constitutive heterochromatin establishment in fission yeast.

In fission yeast, Schizosaccharomyces pombe, constitutive heterochromatin defined by methylation of histone H3 lysine 9 (H3K9me) and its binding protein Swi6/HP1 localizes at the telomere, centromere, and mating-type loci. These loci contain DNA sequences called dg and dh, and the RNA interference (RNAi)-dependent system establishes and maintains heterochromatin at dg/dh. Bi-directional transcription at dg/dh induced by RNA polymerase II is critical in RNAi-dependent heterochromatin formation because the transcribed RNAs provide substrates for siRNA synthesis and a platform for assembling RNAi factors. However, a regulator of dg/dh transcription during the establishment of heterochromatin is not known. Here, we found that a zinc-finger protein Moc3 localizes dh and activates dh-forward transcription in its zinc-finger-dependent manner when heterochromatin structure or heterochromatin-dependent silencing is compromised. However, Moc3 does not localize at normal heterochromatin and does not activate the dh-forward transcription. Notably, the loss of Moc3 caused a retarded heterochromatin establishment, showing that Moc3-dependent dh-forward transcription is critical for RNAi-dependent heterochromatin establishment. Therefore, Moc3 is a transcriptional activator that induces RNAi to establish heterochromatin.

Successful treatment of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa after allogeneic hematopoietic stem cell transplantation with colistin and amikacin inhalation therapy.

Pseudomonas aeruginosa is a Gram-negative bacillus that often causes severe infections during immunosuppression in patients with hematologic malignancies. P. aeruginosa can easily acquire drug resistance, and often develops into multidrug-resistant P. aeruginosa (MDRP). Although many antibiotics are used in combination to treat MDRP infections, colistin and amikacin are less likely to be transferred to the lungs, and inhalation therapy may be used. Herein, we report a Case of pneumonia caused by MDRP after allogeneic hematopoietic stem cell transplantation (HSCT) treated with inhaled colistin and amikacin. This 61-year-old female patient was diagnosed with myelodysplastic syndromes and underwent allogeneic HSCT from an 8/8 HLA-matched unrelated donor after reduced-intensity conditioning. On the day of the stem cell infusion, the patient's sputum culture was found to be positive for MDRP. The patient subsequently developed bacteremia, pneumonia, and lung abscess caused by MDRP, and we administered multidrug antibiotic therapy including colistin and amikacin inhalation therapy. The patient's blood cultures were subsequently turned negative, and the lung abscess disappeared. To our knowledge, this is the first case of MDRP pneumonia after HSCT in which colistin and amikacin inhalation therapy was effective.

[The efficacy of alemtuzumab for pure red cell aplasia associated with autoimmune polyendocrine syndrome type 1].

We present a case of a 41-year-old woman who was diagnosed with autoimmune polyendocrine syndrome type 1 (APS-1) at the age of 2. She developed severe anemia and was diagnosed with pure red cell aplasia (PRCA) and T-cell large granular lymphocyte leukemia at the age of 34. The pathogenesis of APS-1 is based on the presence of an inactive mutation in the autoimmune regulator gene on thymic medullary epithelial cells. It is thought that the autoimmune T cells generated by impaired negative selection in the thymus induce PRCA. The patient was treated with immunosuppressive therapy (ciclosporin, antithymocyte globulin, prednisolone, and cyclophosphamide) for a long time by her previous doctor. After a long period of remission and exacerbation, she became dependent on blood transfusion approximately at the age of 40 and was transferred to our hospital. At our hospital, alemtuzumab treatment resulted in the disappearance of large granular lymphocytes and improvement of anemia. We report this case as a valuable demonstration of the efficacy of alemtuzumab for treating PRCA associated with APS-1.

[Transformation of follicular lymphoma to classical Hodgkin lymphoma during observation].

A 44-year-old female was diagnosed with follicular lymphoma (FL), grade 3A stage III, by right cervical lymph node biopsy at the age of 43 years. The patient chose to not receive the treatment despite the high tumor burden. The patient came back after 18 months with respiratory distress and had systemic infiltration and pleural effusion. Positron emission tomography (PET)/computed tomography (CT) showed fluorine-18 deoxyglucose accumulation with maximum standardized uptake value ranging from 10 to 18 in bone marrow, liver, spleen, lung, and systemic lymph nodes (cervical, supraclavicular, infraclavicular, axillary, mediastinal, hilar, para-aortic, iliac, and inguinal). Left inguinal lymph node biopsy revealed mixed cellularity classical Hodgkin lymphoma (CHL), which was thought to be an FL transformation or a composite condition. The patient was treated with A + AVD and achieved lymph node shrinkage as well as improvement of tumor fever and pleural effusion. Interim PET/CT showed improvement in most parts after two courses; however, it revealed some new or progressive lesions in the bone marrow and left cervical lymph nodes. Left cervical lymph node biopsy revealed nodular sclerosis CHL. The patient was treated with ESHAP, which resulted in stable disease; following this, the patient was treated with nivolumab, which was highly effective. FL transformation to CHL is rare, and this is the first report of such transformation without treatment.

The Effects of Downhill Running and Maturation on Histological and Morphological Properties of Tendon and Enthesis in Mice.

To date, it remains unclear how overuse affects the tendons and entheses at different stages of maturation. Therefore, we evaluated histological and morphological changes in the tendons and entheses in adolescent (4-week-old) and adult mice (8-week-old) by performing flat-land and downhill running exercises. The mice were divided into the Sedentary, High Flat (flat-land high-speed running; concentric-contraction exercise), Low Down (downhill low-speed running; eccentric-contraction exercise), and High Down (downhill high-speed running; eccentric-contraction exercise) groups. Histological changes and inflammatory factor expressions were compared in the entheses and tendons after 4 weeks of exercise. Downhill, but not flat-land high-speed running, induced muscle-tendon complex hypertrophy in both adolescent and adult mice. Histological enthesis changes were induced in both groups during downhill running but were less pronounced in adult mice. Conversely, no significant cell aggregation or fiber orientation changes were observed in the tendon, but increased inflammatory factors were observed in both groups, with significantly higher expression in the tendons of adult mice. Downhill running induced histological and morphological enthesis changes and inflammatory factor increase in the tendons, regardless of running speed variations. These results may help elucidate the pathogenesis of enthesopathy and tendinopathy, which have different pathophysiologies despite having the same pathogenetic factors.

Heterozygous Dnmt3a R878C induces expansion of quiescent hematopoietic stem cell pool.

Somatic mutation of DNMT3A (DNA methyltransferase 3 alpha) is implicated in the development of a wide range of hematological disorders, including clonal hematopoiesis of indeterminate potential. To elucidate the functional roles of endogenous levels of a DNMT3A R882 mutant, we generated a novel Dnmt3a R878C conditional knock-in mouse model. In contrast to viable heterozygotes, mice homozygous for the Dnmt3a R878C mutation in the hematopoietic system were not viable (Dnmt3a R878C is homologous to human DNMT3A R882C). Hematopoietic cell-specific heterozygous expression of Dnmt3a R878C led to significant expansion of adult quiescent hematopoietic stem cells (HSCs); however, these mice had no hematological malignancies. The expanding HSC population in heterozygous Dnmt3a R878C knock-in mice had an accumulation of G0-phase cells. In contrast to aberrantly enhanced self-renewal capacity in vitro, heterozygous Dnmt3a R878C knock-in HSCs had no competitive repopulating advantage in vivo over wild-type HSCs. Considering the capacity of the heterozygous Dnmt3a R878C mutant for HSC pool expansion, our Dnmt3a R878C knock-in mouse line is a useful platform on which to dissect the pathophysiology of clonal hematopoiesis. This mouse line can also help to elucidate the biological and molecular actions of DNMT3A mutations in the malignant transformation of normal HSCs.