SENP3 Promotes Mantle Cell Lymphoma Development through Regulating Wnt10a Expression.

OBJECTIVE: SUMO-specific protease 3 (SENP3), a member of the SUMO-specific protease family, reverses the SUMOylation of SUMO-2/3 conjugates. Dysregulation of SENP3 has been proven to be involved in the development of various tumors. However, its role in mantle cell lymphoma (MCL), a highly aggressive lymphoma, remains unclear. This study was aimed to elucidate the effect of SENP3 in MCL. METHODS: The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR, Western blotting or immunohistochemistry. MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs. Cell proliferation was assessed by CCK-8 assay, and cell apoptosis was determined by flow cytometry. mRNA sequencing (mRNA-seq) was used to investigate the underlying mechanism of SENP3 knockdown on MCL development. A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo. RESULTS: SENP3 was upregulated in MCL patient samples and cells. Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis. Meanwhile, the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown. Furthermore, the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model. CONCLUSION: SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.

Prognostic Role of Serum Albumin Level in Patients with Lymphoma Undergoing Autologous Stem Cell Transplantation.

BACKGROUND High-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) plays a crucial role in the therapy of patients with lymphoma. This retrospective study aimed to analyze prognostic factors in patients undergoing HDT/ASCT for lymphoma. MATERIAL AND METHODS We included patients with lymphoma who underwent HDT/ASCT at our center. Time-to-event outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed with the Kaplan-Meier method and log-rank test. Receiver operating characteristic (ROC) curve analysis and Cox proportional hazard regression analysis were performed to explore the prognostic value of different factors. RESULTS A total of 113 patients with lymphoma were included. Patients with low serum albumin levels (<37 g/L) before transplantation had significantly lower PFS and OS (P<0.01). Albumin levels before transplantation significantly predicted early progression (progressed within 1 year) after transplantation (AUC=0.706, P=0.003). Multivariate Cox analysis indicated that low albumin level (hazard ratio [HR] 3.19, 95% confidence interval [CI] 1.54-6.63; P=0.002) and age >60 years (HR 2.92, 95% CI 1.27-6.71; P=0.012) were independent risk factors for PFS. Total protein <60 g/L was an independent risk factor for OS (HR 3.57, 95% CI 1.45-8.78; P=0.006). CONCLUSIONS Low albumin level before transplantation was an independent risk factor in patients with lymphoma undergoing HDT/ASCT. Intense care and effective maintenance therapy after transplantation are required for patients with low albumin levels.

SENP1 promotes MCL pathogenesis through regulating JAK-STAT5 pathway and SOCS2 expression.

Mantle cell lymphoma (MCL) is highly aggressive and its treatment remains challenging, understanding its pathogenesis is critical for future targeted therapy. SUMO specific proteases 1 (SENP1) is an important protein that regulates the balance between SUMOylation and deSUMOylation. We found that SENP1 was upregulated in MCL patient samples and cell lines. Knockdown of SENP1 could inhibit the proliferation and promote the apoptosis of MCL cells. We also found that SENP1 knockdown caused inhibition of the JAK-STAT5 pathway and upregulation of tumor suppressor cytokine signaling 2 (SOCS2). Moreover, MCL tumor growth in vivo was significantly suppressed after SENP1 knockdown in a xenograft nude mouse model. In summary, our results showed that SENP1 is involved in the pathogenesis of MCL and may be a potential therapeutic target.

Comparison of the efficacy of hematopoietic stem cell mobilization regimens: a systematic review and network meta-analysis of preclinical studies.

BACKGROUND: Mobilization failure may occur when the conventional hematopoietic stem cells (HSCs) mobilization agent granulocyte colony-stimulating factor (G-CSF) is used alone, new regimens were developed to improve mobilization efficacy. Multiple studies have been performed to investigate the efficacy of these regimens via animal models, but the results are inconsistent. We aim to compare the efficacy of different HSC mobilization regimens and identify new promising regimens with a network meta-analysis of preclinical studies. METHODS: We searched Medline and Embase databases for the eligible animal studies that compared the efficacy of different HSC mobilization regimens. Primary outcome is the number of total colony-forming cells (CFCs) in per milliliter of peripheral blood (/ml PB), and the secondary outcome is the number of Lin- Sca1+ Kit+ (LSK) cells/ml PB. Bayesian network meta-analyses were performed following the guidelines of the National Institute for Health and Care Excellence Decision Support Unit (NICE DSU) with WinBUGS version 1.4.3. G-CSF-based regimens were classified into the SD (standard dose, 200-250 µg/kg/day) group and the LD (low dose, 100-150 µg/kg/day) group based on doses, and were classified into the short-term (2-3 days) group and the long-term (4-5 days) group based on administration duration. Long-term SD G-CSF was chosen as the reference treatment. Results are presented as the mean differences (MD) with the associated 95% credibility interval (95% CrI) for each regimen. RESULTS: We included 95 eligible studies and reviewed the efficacy of 94 mobilization agents. Then 21 studies using the poor mobilizer mice model (C57BL/6 mice) to investigate the efficacy of different mobilization regimens were included for network meta-analysis. Network meta-analyses indicated that compared with long-term SD G-CSF alone, 14 regimens including long-term SD G-CSF + Me6, long-term SD G-CSF + AMD3100 + EP80031, long-term SD G-CSF + AMD3100 + FG-4497, long-term SD G-CSF + ML141, long-term SD G-CSF + desipramine, AMD3100 + meloxicam, long-term SD G-CSF + reboxetine, AMD3100 + VPC01091, long-term SD G-CSF + FG-4497, Me6, long-term SD G-CSF + EP80031, POL5551, long-term SD G-CSF + AMD3100, AMD1300 + EP80031 and long-term LD G-CSF + meloxicam significantly increased the collections of total CFCs. G-CSF + Me6 ranked first among these regimens in consideration of the number of harvested CFCs/ml PB (MD 2168.0, 95% CrI 2062.0-2272.0). In addition, 7 regimens including long-term SD G-CSF + AMD3100, AMD3100 + EP80031, long-term SD G-CSF + EP80031, short-term SD G-CSF + AMD3100 + IL-33, long-term SD G-CSF + ML141, short-term LD G-CSF + ARL67156, and long-term LD G-CSF + meloxicam significantly increased the collections of LSK cells compared with G-CSF alone. Long-term SD G-CSF + AMD3100 ranked first among these regimens in consideration of the number of harvested LSK cells/ml PB (MD 2577.0, 95% CrI 2422.0-2733.0). CONCLUSIONS: Considering the number of CFC and LSK cells in PB as outcomes, G-CSF plus AMD3100, Me6, EP80031, ML141, FG-4497, IL-33, ARL67156, meloxicam, desipramine, and reboxetine are all promising mobilizing regimens for future investigation.

Prognostic Significance of CD56 Antigen Expression in Patients with De Novo Non-M3 Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous group of disorders with distinct characteristics and prognoses. Although cytogenetic changes and gene mutations are associated with AML prognosis, there is a need to identify further factors. CD56 is considered a prognostic factor for AML, which is abnormally expressed in leukemia cells. However, a clear consensus for this surface molecule is lacking, which has prompted us to investigate its prognostic significance. Bone marrow samples of de novo non-M3 AML were collected to detect CD56 expression using multiparameter flow cytometry (FCM). As a result, the CD56 expression in de novo non-M3 AML was found to be significantly higher than that in acute lymphoma leukemia (ALL, P = 0.017) and healthy controls (P = 0.02). The X-Tile program produced a CD56 cutoff point at a relative expression level of 24.62%. Based on this cutoff point, high CD56 expression was observed in 29.21% of de novo non-M3 AML patients. CD56-high patients had a poor overall survival (OS, P = 0.015) compared to CD56-low patients. Bone marrow transplantation (BMT) improved OS (P = 0.004), but a poor genetic risk was associated with an inferior OS (P = 0.002). Compared with CD56-low patients, CD56-high patients had lower peripheral blood platelet (PLT) counts (P = 0.010). Our research confirmed that high CD56 expression is associated with adverse clinical outcomes in de novo non-M3 AML patients, indicating that CD56 could be used as a prognostic marker for a more precise stratification of de novo non-M3 AML patients.

Efficacy and safety of new anti-CD20 monoclonal antibodies versus rituximab for induction therapy of CD20+ B-cell non-Hodgkin lymphomas: a systematic review and meta-analysis.

Rituximab combined with chemotherapy is the first-line induction therapy of CD20 positive B-cell non-Hodgkin lymphomas (CD20+ B-NHL). Recently new anti-CD20 monoclonal antibodies (mAbs) have been developed, but their efficacy and safety compared with rituximab are still controversial. We searched MEDLINE, Embase, and Cochrane Library for eligible randomized controlled trials (RCTs) that compared new anti-CD20 mAbs with rituximab in induction therapy of B-NHL. The primary outcomes are progression-free survival (PFS) and overall survival (OS), additional outcomes include event-free survival (EFS), disease-free survival (DFS), overall response rate (ORR), complete response rate (CRR) and incidences of adverse events (AEs). Time-to-event data were pooled as hazard ratios (HRs) using the generic inverse-variance method and dichotomous outcomes were pooled as odds ratios (ORs) using the Mantel-Haenszel method with their respective 95% confidence interval (CI). Eleven RCTs comprising 5261 patients with CD20+ B-NHL were included. Compared with rituximab, obinutuzumab significantly prolonged PFS (HR 0.84, 95% CI 0.73-0.96, P = 0.01), had no improvement on OS, ORR, and CRR, but increased the incidences of serious AEs (OR 1.29, 95% CI 1.13-1.48, P < 0.001). Ofatumumab was inferior to rituximab in consideration of ORR (OR 0.73, 95% CI 0.55-0.96, P = 0.02), and had no significant differences with rituximab in regard to PFS, OS and CRR. 131I-tositumomab yielded similar PFS, OS, ORR and CRR with rituximab. 90Y-ibritumomab tiuxetan increased ORR (OR 3.07, 95% CI 1.47-6.43, P = 0.003), but did not improve PFS, DFS, OS and CRR compared with rituximab. In conclusion, compared with rituximab in induction therapy of CD20+ B-NHL, obinutuzumab significantly improves PFS but with higher incidence of AEs, ofatumumab decreases ORR, 90Y-ibritumomab tiuxetan increases ORR.

Zfp521 SUMOylation facilities erythroid hematopoietic reconstitution under stress.

Zinc finger protein 521 (Zfp521) is a key transcriptional factor in regulation of hematopoiesis. SUMOylation, a protein post-translational modification process, plays important roles in various biological process including hematopoiesis. However, whether Zfp521 can be SUMOylated and how it affects hematopoiesis is unknown. In this study, we confirmed that Zfp521 can be modified by SUMO1 and lysine 1146 was the primary SUMOylation site. Under homeostatic condition, Zfp521 SUMOylation-deficient mice had normal mature blood cells and primitive cells. However, in bone marrow (BM) transplantation assay, recipient mice transplanted with BM cells from Zfp521 SUMOylation-deficient mice had a significantly decreased R2 population of erythroid lineage in BM and spleen compared with those transplanted with BM cells from wild-type mice. Our results found a novel function of Zfp521 SUMOylation in erythroid reconstitution under stress, which might be a new therapeutic target in future.

Resveratrol: Review on its discovery, anti-leukemia effects and pharmacokinetics.

Resveratrol, found in variety of plants, is a natural stilbene structure polyphenol. It has various pharmacological effects, such as antioxidation, anti-aging, anti-inflammation, anti-cancer, antiobesity, anti-diabetes, cardioprotection, neuroprotection. Recently, anti-leukemia activities of resveratrol has been studied extensively via its effects on a variety of biological processes involving cell proliferation, apoptosis, autophagy. Current treatments of leukemia mainly rely on intensive chemotherapy or hematopoietic stem cell transplantation, however, these treatments are still with poor survival and high treatment-related mortality. Therefore, it is extremely needed to find relatively non-toxic medicines with minimal side effects but sufficient therapeutic efficacy. Resveratrol is one such potential candidate owing to its reported anti-leukemia effect. In this review, we summarized resveratrol's discovery, sources and isolation methods, administration methods, effects in different types of leukemia, pharmacokinetics and toxicities, aiming to exploit resveratrol as a potential drug candidate for anti-leukemia.