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p97/VCP is an endoplasmic reticulum (ER)‐associated protein that belongs to the AAA (ATPases associated with diverse cellular activities) ATPase family. It has a variety of cellular functions including ER‐associated protein degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles of p97/VCP and its potential as a therapeutic target in several cancer subtypes including multiple myeloma (MM). We conducted a cell‐based compound screen to exploit novel small compounds that have cytotoxic activity in myeloma cells. Among approximately 2000 compounds, OSSL_325096 showed relatively strong antiproliferative activity in MM cell lines (IC50, 100‐500 nmol/L). OSSL_325096 induced apoptosis in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. Accumulation of poly‐ubiquitinated proteins, PERK, CHOP, and IREα, was observed in MM cell lines treated with OSSL_325096, suggesting that it induces ER stress in MM cells. OSSL_325096 has a similar chemical structure to DBeQ, a known p97/VCP inhibitor. Knockdown of the gene encoding p97/VCP induced apoptosis in myeloma cells, accompanied by accumulation of poly‐ubiquitinated protein. IC50 of OSSL_325096 to myeloma cell lines were found to be lower (0.1‐0.8 μmol/L) than those of DBeQ (2‐5 μmol/L). In silico protein–drug‐binding simulation suggested possible binding of OSSL_325096 to the ATP binding site in the D2 domain of p97/VCP. In cell‐free ATPase assays, OSSL_325096 showed dose‐dependent inhibition of p97/VCP ATPase activity. Finally, OSSL_325096 inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti‐myeloma activity, at least in part through p97/VCP inhibition. We found that OSSL_325096 showed relatively strong antiproliferative activity in myeloma cell lines, including a bortezomib‐resistant cell line and primary myeloma cells purified from patients. OSSL_325096 showed dose‐dependent inhibition of p97/VCP ATPase activity and inhibited the growth of subcutaneous myeloma cell tumors in vivo. The present data suggest that OSSL_325096 exerts anti‐myeloma activity, at least in part through p97/VCP inhibition.

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for 30% of non‐Hodgkin lymphomas. Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by Spi1, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non‐germinal center B‐cell‐like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in vivo, we generated conditional Spi1 knockout mice using Cγ1‐Cre mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B‐cell lymphomas. In contrast, no wild‐type mice developed B‐cell lymphoma. In addition, RNA‐seq analysis of lymphoma cells from Cγ1‐Cre Spi1F/F mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3 weeks. Lentiviral‐transduced Spi1 rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B‐cell lymphoma development. PU.1, particularly the non‐germinal center B‐cell‐like (GCB) type, is downregulated in human lymphoma cells. Conditional knockout of Spi1 in mature B cells induces B cell lymphoma in mice.

Paroxysmal nocturnal hemoglobinuria (PNH) is a lifelong, clonal hematologic disease posing life-threatening risks if untreated. The prognosis for PNH has improved with the advent of C5 inhibitors, which are now the standard of care where available. As treatment options continue to expand, healthcare providers can better address both PNH management and the impact of treatment on patients' daily lives. To investigate the burden of disease and key factors taken into consideration when patients with PNH choose their preferred treatment, we conducted an in-depth patient interview survey. Of survey participants ( N  = 30), 70.0% were receiving intravenous C5 inhibitors. Notably, 56.7% of all patients reported needing ≥ 1 hospital visit per month, and 46.7% required a day off from work or school for visits (33.3% among those receiving intravenous C5 inhibitors). A frequently reported burden of PNH treatment was financial concern, including the cost of treatment, hospital visits, and the negative impact on income. Additionally, burden related to waiting times and distance from the hospital and the overall time spent on outpatient PNH care were identified with similar results for patients receiving intravenous C5 inhibitors. These results suggest that the time and effort to get to treatment centers and the time required to receive treatment for PNH were critical unmet needs in PNH care. Our study indicates that persistent burdens associated with current PNH care should be taken into account alongside therapeutic effectiveness when making treatment decisions. Further analysis with a larger sample size is required to confirm these findings.

Background Lisocabtagene maraleucel (liso‐cel) is a CD19‐directed chimeric antigen receptor T‐cell therapy for patients with relapsed or refractory large B‐cell lymphoma. Methods In this retrospective study involving 22 patients, we evaluated the association between peripheral blood CD4/CD8 ratios and the occurrence of out‐of‐specification (OOS) products during manufacturing. Expanded access protocols have permitted the infusion of OOS products, despite their failure to meet commercial release criteria, under close regulatory oversight. Results Five patients who received OOS products had significantly lower CD4/CD8 ratios (median 0.22 vs. 0.46; p = 0.008). Conclusion Our findings suggest that a low CD4/CD8 ratio (below one‐third) may be a predictive marker for OOS outcomes, potentially supporting patient selection and treatment planning. Therefore, prospective validation using a larger cohort is warranted.

(1) Background: multiple myeloma patients have benefited from bortezomib therapy, though it has often been discontinued owing to diarrhea. The objective of this study was to verify serum bortezomib concentration in the emergence of diarrhea. (2) Methods: this prospective, observational case-control, and monocentric study was performed with an approval by the Ethics Committee of Kumamoto University Hospital in 2015 (No. 1121) from February 2015 to April 2017. (3) Results: twenty-four patients with bortezomib therapy were recruited; eight patients (33.3%) developed diarrhea at day 3 as median. Median measured trough bortezomib concentration at 24 h after first or second dose for patients with or without diarrhea was 0.87 or 0.48 ng/mL, respectively (p = 0.04, Wilcoxon signed rank test). Receiver operation characteristic (ROC) analysis produced the cut-off concentration of 0.857 ng/mL (area under the ROC curve of 0.797, sensitivity of 0.625, specificity of 0.875). The survival curves between patients with and without diarrhea were similar (p = 0.667); those between patients with higher and lower concentration than median value (0.61 ng/mL) were also similar (p = 0.940). (4) Conclusions: this study indicated the possible involvement of serum bortezomib concentration in the emergence of diarrhea in bortezomib therapy in patients with multiple myeloma.

Skeletal complications represent major clinical problems in multiple myeloma (MM). MM cells are known to induce differentiation of osteoclasts and inhibit osteoblasts. Receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) are key molecules for osteoclastogenesis. Although OPG interacts with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the contribution of TRAIL to skeletal-related events (SRE) remains a matter of debate. In the present study, we examined the role of TRAIL in MM bone lesions. Myeloma cells were purified from 56 MM patients by CD138-immunomagnetic beads. TRAIL, DKK-1 and MIP1α RNA expression in purified MM cells was analyzed by real-time PCR. Immunohistochemistry of TRAIL was performed on paraffin-embedded plasmacytoma tissue sections. The concentration of TRAIL in the serum and bone marrow plasma from MM patients was analyzed by ELISA. TRAIL expression was significantly higher in MM cells than in plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS). TRAIL staining was detected in the cytoplasm of myeloma cells. TRAIL expression in MM cells correlated with bone marrow plasma TRAIL concentration. TRAIL expression had a positive correlation with osteolytic markers, such as serum calcium and urinary deoxypyridinoline. These results suggest that TRAIL, produced from myeloma cells, may play an important role in bone resorption of MM patients. Inhibition of this pathway may lead to development of a new therapeutic approach preventing bone resorption in MM.