CD30 protects EBV-positive diffuse large B-cell lymphoma cells against mitochondrial dysfunction through BNIP3-mediated mitophagy.

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (EBV+ DLBCL) predicts poor prognosis and CD30 expression aggravates the worse consequences. Here, we reported that CD30 positivity was an independent prognostic indicator in EBV+ DLBCL patients in a retrospective cohort study. We harnessed CRISPR/Cas9 editing to engineer the first loss-of-function models of CD30 deficiency to identify that CD30 was critical for EBV+ DLBCL growth and survival. We established a pathway that EBV infection mediated CD30 expression through EBV-encoded latent membrane protein 1 (LMP1), which involved NF-κB signaling. CRISPR CD30 knockout significantly repressed BCL2 interacting protein 3 (BNIP3) expression and co-IP assay indicated a binding between CD30 and BNIP3. Moreover, silencing of CD30 induced mitochondrial dysfunction and suppressed mitophagy, resulting in the accumulation of damaged mitochondria by depressing BNIP3 expression. Additionally, CRISPR BNIP3 knockout caused proliferation defects and increased sensitivity to apoptosis. All the findings reveal a strong relationship between mitophagy and adverse prognosis of EBV+ DLBCL and discover a new regulatory mechanism of BNIP3-mediated mitophagy, which may help develop effective treatment regimens with anti-CD30 antibody brentuximab vedotin to improve the prognosis of CD30+ EBV+ DLBCL patients.

MYC-induced cytidine metabolism regulates survival and drug resistance via cGas-STING pathway in mantle cell lymphoma.

Lymphocyte proliferation and tumourigenesis are dependent on nucleotide synthesis to support DNA, RNA and phospholipid synthesis. Here, we identified that reprogramming of nucleotide metabolism as an important factor divides mantle cell lymphoma (MCL) into two groups with different transcriptional signalling pathways and varying prognoses. We establish a nucleotide metabolism-related prognostic model that includes six genes with different regression coefficients, which significantly predicts prognosis for MCL patients (p < 0.0001). Of these six genes, de novo CTP synthesis pathway enzyme CTPS1 whose inhibitor (STP938) is already in clinical trials for relapsed/refractory lymphomas (NCT05463263) has the highest regression coefficient. An increase in CTPS1 expression predicts adverse overall survival and progression-free survival with independent prognostic significance in 105 primary MCL samples and GEO database (GSE93291). CRISPR CTPS1 knockout causes DNA damage and proliferation defects in MCL. Additionally, MYC positively regulates CTPS1 expression, and TP53-aberrant and ibrutinib-resistant MCL cells also rely on cytidine metabolism. Furthermore, besides the obvious decreased CTP pool caused by CTPS1 deficiency, CTPS1 inhibition may also induce immune-related responses via activating dsDNA-cGAS-STING pathway, which plays a crucial role in impeding tumour growth in MCL patients.

Comparison of microendoscopic discectomy and open discectomy for single-segment lumbar disc herniation.

BACKGROUND: Lumbar disc herniation is a common disease. Endoscopic treatment may have more advantages than traditional surgery. AIM: To compare the clinical efficacy and safety of microendoscopic discectomy (MED) and open discectomy with lamina nucleus enucleation in the treatment of single-segment lumbar intervertebral disc herniation. METHODS: Ninety-six patients who were operated at our hospital were selected for this study. Patients with single-segment lumbar disc herniation were admitted to the hospital from March 2018 to March 2019 and were randomly divided into the observation group and the control group with 48 cases in each group. The former group underwent lumbar discectomy and the latter underwent laparotomy and nucleus pulpectomy. Surgical effects were compared between the two groups. RESULTS: In terms of surgical indicators, the observation group had a longer operation time, shorter postoperative bedtime and hospital stay, less intraoperative blood loss, and smaller incision length than the control group (P < 0.05). The excellent recovery rate did not differ significantly between the observation group (93.75%) and the control group (91.67%). Visual analogue scale pain scores were significantly lower in the observation group than in the control group at 1 d, 3 d, 1 mo, and 6 mo after surgery (P < 0.05). The incidence of complications was significantly lower in the observation group than in the control group (6.25% vs 22.92%, P < 0.05). CONCLUSION: Both MED and open discectomy can effectively improve single-segment lumbar disc herniation, but MED is associated with less trauma, less bleeding, and a lower incidence of complications.