SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3.

The H3K4 methyltransferase SETD1A plays a crucial role in leukemia cell survival through its noncatalytic FLOS domain-mediated recruitment of cyclin K and regulation of DNA damage response genes. In this study, we identify a functional nuclear localization signal in and interaction partners of the FLOS domain. Our screen for FLOS domain-binding partners reveals that the SETD1A FLOS domain binds mitosis-associated proteins BuGZ/BUB3. Inhibition of both cyclin K and BuGZ/BUB3-binding motifs in SETD1A shows synergistic antileukemic effects. BuGZ/BUB3 localize to SETD1A-bound promoter-TSS regions and SETD1A-negative H3K4me1-positive enhancer regions adjacent to SETD1A target genes. The GLEBS motif and intrinsically disordered region of BuGZ are required for both SETD1A-binding and leukemia cell proliferation. Cell-cycle-specific SETD1A restoration assays indicate that SETD1A expression at the G1/S phase of the cell cycle promotes both the expression of DNA damage response genes and cell cycle progression in leukemia cells.

SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia.

Histone methyltransferase SETD1A is critical for acute myeloid leukemia (AML) cell survival, but the molecular mechanism driving SETD1A gene regulation remains elusive. To delineate the role of SETD1A, we utilize a protein degrader technology to induce rapid SETD1A degradation in AML cell lines. SETD1A degradation results in immediate downregulation of transcripts associated with DNA repair and heme biosynthesis pathways. CRISPR-based functional analyses and metabolomics reveal an essential role of SETD1A to maintain mitochondrial respiration in AML cells. These SETD1A targets are enriched in head-to-head (H2H) genes. SETD1A degradation disrupts a non-enzymatic SETD1A domain-dependent cyclin K function, increases the Ser5P RNA polymerase II (RNAPII) at the transcriptional start site (TSS), and induces the promoter-proximal pausing of RNAPII in a strand-specific manner. This study reveals a non-enzymatic role for SETD1A in transcriptional pause release and provides insight into the mechanism of RNAPII pausing and its function in cancer.

Characteristics of cutaneous adverse drug reactions caused by triple-combination drug therapy used for Helicobacter pylori eradication.

Cutaneous adverse drug reactions (cADR) should be appropriately managed in drug administration. LANSAP® , Rabecure® and VONOSAP® are currently used for Helicobacter pylori eradication therapy. Here, we examined the characteristics of cADR caused by these drugs using data from the Pharmaceuticals and Medical Devices Agency (PMDA). Periods subject to analyses were set according to the year of release of these drugs: (i) from 2008 to 2017 for LANSAP; (ii) from 2014 to 2017 for Rabecure; and (iii) 2017 for VONOSAP. Among all cADR reported to the PMDA, those attributed to LANSAP, Rabecure and VONOSAP accounted for 2.3%, 1.0% and 3.6% of cases, respectively. cADR occurred in patients aged in their 20s or older, with the oldest patients aged in their 60s. Numbers of male and female patients were 28 and 70 for LANSAP, eight and 14 for Rabecure and three and 16 for VONOSAP, respectively. Statistical analyses revealed significant sex differences for LANSAP (P = 0.022) and VONOSAP (P = 0.012), but not for Rabecure (P = 0.729). LANSAP, Rabecure or VONOSAP caused erythema multiforme in the largest population of patients and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in three patients. Ratios of SJS/TEN were 0.0-5.3% for LANSAP, Rabecure or VONOSAP, but 11.5-44.8% for the corresponding single constituent drugs other than vonoprazan. In conclusion, female sex appears to represent a risk factor for cADR attributed to H. pylori eradication therapy using LANSAP or VONOSAP, although H. pylori eradication therapy without these drugs rarely causes severe cADR.

Suppressive Effects of Mesenchymal Stem Cells in Adipose Tissue on Allergic Contact Dermatitis.

BACKGROUND: Allergic contact dermatitis (ACD), which is accelerated by interferon (IFN)-γ and suppressed by interleukin (IL)-10 as regulators, is generally self-limited after removal of the contact allergen. Adipose tissue-derived multipotent mesenchymal stem cells (ASCs) potentially exert immunomodulatory effects. Considering that subcutaneous adipose tissue is located close to the site of ACD and includes mesenchymal stem cells (MSCs), the MSCs in adipose tissue could contribute to the self-limiting course of ACD. OBJECTIVE: The aims of the present study were to elucidate the effects of MSCs in adipose tissue on ACD and to examine any cytokine-mediated mechanisms involved. METHODS: Ear thickness in a C57BL/6 mouse model of ACD using contact hypersensitivity (CHS) elicited by 2,4,6-trinitro-1-chlorobenzene was evaluated as a marker of inflammation level. Five and nine mice were injected with ASCs and phosphate-buffered saline (PBS), respectively. After ASC or PBS injection, real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed. RESULTS: Histology showed that CHS was self-limited and ear thickness was suppressed by ASCs in a dose-dependent manner. IFN-γ expression in the elicited skin site and regional lymph nodes was significantly lower in ASC-treated mice than in control mice. IL-10 expression did not differ between treated and control mice. The suppressive effects of ASCs on CHS response did not differ between IL-10 knock-out C57BL/6 mice and wild-type mice. CONCLUSION: The present findings suggest that MSCs in adipose tissue may contribute to the self-limiting course of ACD through decreased expression of IFN-γ, but not through increased expression of IL-10.

Switching of biologics in psoriasis: Reasons and results.

Efficacy and safety profiles of biologics have been established for moderate to severe psoriasis. However, inefficacy or adverse events sometimes require changing the treatment to other biologics. Here, we examine the effectiveness of this strategy. We retrospectively investigated cases requiring switching biologics. We enrolled 275 psoriatic patients treated with biologics between January 2010 and December 2014 in our hospital. Of these, 51 required a switch to another biologic. First-line therapies were infliximab (IFX, n = 26), adalimumab (ADA, n = 18) and ustekinumab (UST, n = 7), and second-line therapies were IFX (n = 5), ADA (n = 21) and UST (n = 25). Reasons for switching were inefficacy (n = 38), adverse events (n = 11) and others (n = 2). The details were primary failure (n = 15), secondary failure (n = 23) and infusion reactions (n = 8). In 49 patients who switched biologics due to inefficacy and adverse events, the mean Psoriasis Area and Severity Index (PASI) score at week 16 was 4.3 for first-line therapies and 2.9 for second-line therapies (P < 0.05). Switching to a second biologic therapy to address the first's inefficacy or adverse events often results in significant improvement in moderate to severe psoriasis.

IL-10-producing regulatory B cells are decreased in patients with psoriasis.

BACKGROUNDS: Interleukin (IL)-10-producing regulatory B cells (B10 cells) have been shown to ameliorate psoriasis in mice. Human B10 progenitor cells are characterized as CD19(+)CD24(hi)CD38(hi) B cells that exert their regulatory functions via the production of IL-10. However, the role of B10 cells in the pathogenesis of psoriasis remains unclear. OBJECTIVES: We examined B10 cells in patients with psoriasis and healthy controls. METHODS: Peripheral blood mononuclear cells were isolated from psoriasis patients without a history of receiving any immunosuppressants during the 6-month period before enrollment in the study. Using flow cytometry, we determined the frequencies of blood B cell subsets, B10 progenitor cells, and B10 cells for 31 patients with psoriasis and 26 healthy controls. RESULTS: Both psoriasis patients and healthy controls showed similar frequencies of total B cells, IgD(+)CD27(-) naïve B cells, and IgD(-)CD27(+) memory B cells. However, the frequency of CD19(+)CD24(hi)CD38(hi) B10 progenitor cells was significantly higher in patients with psoriasis than in the healthy controls. In contrast, the frequency of B10 cells in patients with psoriasis was significantly lower than that in healthy controls. Furthermore, treatment with immunosuppressants resulted in a decrease in B10 progenitor cells and an increase in B10 cells. CONCLUSION: B10 progenitor cells were increased, while IL-10-producing regulatory B10 cells were decreased in patients with psoriasis, suggesting that B10 cells may be functionally impaired in patients with psoriasis.

Adalimumab markedly improves enthesitis in patients with psoriatic arthritis: Evaluation with a magnetic resonance imaging scoring system.

Psoriatic arthritis (PsA), a seronegative arthropathy, may often result in progressive joint damage without treatment, leading to disability and impaired quality of life. Early therapeutic intervention of PsA is therefore crucial before the development of irreversible joint damage. Because psoriatic skin lesions generally precede the onset of PsA, dermatologists occupy an important position in treating patients with early PsA. This study aimed to evaluate the efficacy of adalimumab in treating joint disease in patients with PsA, using the PsA magnetic resonance imaging scoring system (PsAMRIS). Five adult Japanese male patients with active PsA were treated with adalimumab. Magnetic resonance imaging was obtained at baseline and 8-32 weeks with 2-3 time points following adalimumab treatment and assessed using PsAMRIS. Adalimumab treatment markedly improved clinical symptoms and disease activities of joint disease, which was confirmed by the reduction of PsAMRIS scores in all patients. Bone marrow edema and periarticular inflammation, reflecting the presence of enthesitis, were dramatically improved at week 8, while improvement of synovitis and flexor tenosynovitis was observed later, at week 24 or 32. However, bone erosion was not improved by adalimumab treatment during the follow-up period. These results indicate that adalimumab treatment is associated with dramatic improvement of enthesitis in patients with PsA, whereas bone erosion may be resistant to such treatment. PsAMRIS appears to be useful for the evaluation of treatment efficacy in PsA.

Ustekinumab treatment in patients with psoriasis undergoing hemodialysis.

Patients with psoriasis undergoing hemodialysis have additional difficulties in treatment compared with general patients. Conventional treatments such as cyclosporin, retinoids and methotrexate are not widely administrated due to the chances of an increase in adverse effects and the possibility of risk to patient survival. Recently, biologic treatments have been recognized as having sufficient efficacy for severe psoriasis with low incidence of organ toxicities. For this reason, biologic treatments may be more preferable for patients on hemodialysis; however, there is not sufficient evidence. We have treated three patients with psoriasis with ustekinumab for 1 year, who had been undergoing hemodialysis. They were previously treated with conventional treatments before ustekinumab treatments; however, they did not respond to these treatments sufficiently. Following treatment with ustekinumab, rapid and maintained improvement in psoriasis was observed. Over the course of treatments, two of the three patients encountered no adverse events during their first year of treatment. The other patient discontinued ustekinumab due to elevated levels of C-reactive protein. These findings suggest that ustekinumab may be an appropriate treatment for patients undergoing hemodialysis who are suffering from psoriasis. However, the risk of developing infection remains higher than in general patients.