SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Genomic mutation patterns and prognostic value in de novo and secondary acute myeloid leukemia: A multicenter study from China.

Acute myeloid leukemia (AML) can manifest as de novo AML (dn-AML) or secondary AML (s-AML), with s-AML being associated with inferior survival and distinct genomic characteristics. The underlying reasons for this disparity remain to be elucidated. In this multicenter study, next-generation sequencing (NGS) was employed to investigate the mutational landscape of AML in 721 patients from June 2020 to May 2023.Genetic mutations were observed in 93.34% of the individuals, with complex variations (more than three gene mutations) present in 63.10% of them. TET2, ASXL1, DNMT3A, TP53 and SRSF2 mutations showed a higher prevalence among older individuals, whereas WT1 and KIT mutations were more commonly observed in younger patients. BCOR, BCORL1, ZRSR2, ASXL1 and SRSF2 exhibited higher mutation frequencies in males. Additionally, ASXL1, NRAS, PPMID, SRSF2, TP53 and U2AF1 mutations were more common in patients with s-AML, which PPM1D was more frequently associated with therapy-related AML (t-AML). Advanced age and hyperleukocytosis independently served as adverse prognostic factors for both types of AML; however, s-AML patients demonstrated a greater number of monogenic adverse prognostic factors compared to dn-AML cases (ASXL1, PPM1D, TP53 and U2AF1 in s-AML vs. FLT3, TP53 and U2AF1 in dn-AML). Age and sex-related gene mutations suggest epigenetic changes may be key in AML pathogenesis. The worse prognosis of s-AML compared to dn-AML could be due to the older age of s-AML patients and more poor-prognosis gene mutations. These findings could improve AML diagnosis and treatment by identifying potential therapeutic targets and risk stratification biomarkers.

Ticlopidine protects hepatic ischemia-reperfusion injury via suppressing ferroptosis.

Hepatic ischemia-reperfusion injury (IRI) is a major cause of liver damage during hepatic resection, transplantation, and other surgical procedures, often leading to graft failure and liver dysfunction. Recent studies have identified ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, as a key contributor to IRI. In this study, we investigated the protective effects of Ticlopidine, a thienopyridine compound and platelet aggregation inhibitor, on hepatic IRI. Using a C57BL/6J mouse model, we demonstrated that prophylactic Ticlopidine treatment significantly reduced necrotic and fibrotic areas in liver tissues, as well as serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST). Prussian Blue staining revealed that Ticlopidine pretreatment decreased iron accumulation in hepatic tissues, whereas markers of lipid peroxidation (malondialdehyde and 4-hydroxynonenal) and ferroptosis (PTGS2) were significantly downregulated. Additionally, Ticlopidine ameliorated inflammatory infiltration as indicated by reduced Gr-1 staining. In vitro, Ticlopidine dose-dependently inhibited ferroptosis induced by various inducers in liver cancer cell lines HUH7 and fibrosarcoma cells HT1080. The protective effects involved partial rescue of lipid peroxidation, significant reduction of ferrous iron levels, and strong protection against mitochondrial damage. These findings suggested that Ticlopidine acts as a broad-spectrum ferroptosis inhibitor, offering a promising therapeutic approach for protecting the liver against IRI.

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.

The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia.

BACKGROUND: Anthracycline combined with cytarabine has been the standard for induction therapy of newly diagnosed acute myeloid leukaemia (AML) for several decades. Due to theoretical advantages, idarubicin (IDA) might be the most effective and tolerable anthracycline. However, there is no evidence that would definitively prove the superiority of IDA over other anthracyclines. OBJECTIVES: To assess the efficacy and safety of IDA versus other anthracyclines in induction therapy of newly diagnosed AML. SEARCH METHODS: We identified relevant randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 8), MEDLINE (from 1946 to 3 August 2014), EMBASE (from 1974 to 3 August 2014), Chinese BioMedical Literature Database (1978 to 3 August 2014), relevant conference proceedings and databases of ongoing trials. SELECTION CRITERIA: RCTs that compared IDA with other anthracyclines in induction therapy of newly diagnosed AML. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of studies according to methodological standards of the Cochrane Collaboration. We estimated hazard ratios (HRs) for time-to-event data outcomes using the inverse variance method, and risk ratios (RRs) for dichotomous data outcomes using the Mantel-Haenszel method. We adopted a fixed-effect model and repeated the main meta-analysis by a random-effects model in a sensitivity analysis. MAIN RESULTS: We identified 2017 references. Ultimately, 27 RCTs (including 22 two-armed RCTs and five three-armed RCTs) involving 9549 patients were eligible. The consolidation treatments adopted in the studies were comparable and had no impact on the results. Overall, the risk of bias of the studies was unclear to high.Eighteen RCTs (N = 6755) assessed IDA versus daunorubicin (DNR). The main meta-analyses showed that IDA compared with DNR prolonged overall survival (OS) (12 studies, 5976 patients; HR 0.90, 95% confidence interval (CI) 0.84 to 0.96, P = 0.0008; high quality of evidence) and disease-free survival (DFS) (eight studies, 3070 patients; HR 0.88, 95% CI 0.81 to 0.96, P = 0.004; moderate quality of evidence), increased complete remission (CR) rate (18 studies, 6692 patients; RR 1.04, 95% CI 1.01 to 1.07, P = 0.009; moderate quality of evidence), and reduced relapse rate (four studies, 1091 patients; RR 0.88, 95% CI 0.80 to 0.98, P = 0.02; moderate quality of evidence), although increased the risks of death on induction therapy (14 studies, 6349 patients; RR 1.18, 95% CI 1.01 to 1.36, P = 0.03; moderate quality of evidence) and grade 3/4 mucositis (five studies, 2000 patients; RR 1.22, 95% CI 1.04 to 1.44, P = 0.02; moderate quality of evidence). There was no evidence for difference in the risks of grade 3/4 cardiac toxicity (six studies, 2795 patients; RR 0.98, 95% CI 0.70 to 1.37, P = 0.91; moderate quality of evidence) and other grade 3/4 adverse events (AEs). None of the studies reported on quality of life (QoL).Eight RCTs (N = 2419) evaluated IDA versus mitoxantrone (MIT). The main meta-analyses showed that there was no evidence for difference between arms in OS (six studies, 2171 patients; HR 0.98, 95% CI 0.89 to 1.08, P = 0.69; high quality of evidence), DFS (four studies, 249 patients; HR 0.88, 95% CI 0.70 to 1.10, P = 0.26; low quality of evidence), CR rate (eight studies, 2411 patients; RR 0.97, 95% CI 0.92 to 1.03, P = 0.32;moderate quality of evidence), the risks of death on induction therapy (five studies, 2055 patients; RR 1.10, 95% CI 0.88 to 1.38, P = 0.39; moderate quality of evidence) and relapse (three studies, 328 patients; RR 0.99, 95% CI 0.80 to 1.22, P = 0.89; moderate quality of evidence). There was no evidence for difference in the risks of grade 3/4 cardiac toxicity (one study, 160 patients; RR 0.67, 95% CI 0.11 to 3.88, P = 0.65; low quality of evidence) and other grade 3/4 AEs. None of the studies reported on QoL.Two RCTs (N = 211) compared IDA with doxorubicin (DOX). Neither study assessed OS. One study showed that there was no evidence for difference in DFS (63 patients; HR 0.62, 95% CI 0.34 to 1.14, P = 0.12; low quality of evidence). The main meta-analysis for CR rate showed an improved CR rate with IDA (two studies, 187 patients; RR 1.28, 95% CI 1.03 to 1.59, P = 0.02; low quality of evidence). Neither study provided data for the risks of death on induction therapy and relapse. One trial showed that there was no evidence for difference in the risk of grade 3/4 cardiac toxicity (one study, 100 patients; RR 0.31, 95% CI 0.01 to 7.39, P = 0.47; very low quality of evidence). Neither study reported on QoL.Two RCTs (N = 1037) evaluated IDA versus zorubicin (ZRB). Neither study assessed OS. One trial showed that there was no evidence for difference in DFS (one study, 155 patients; HR 1.25, 95% CI 0.83 to 1.88, P = 0.29; low quality of evidence). The main meta-analyses for CR and death on induction therapy both showed that there was no evidence for difference (CR rate: two studies, 964 patients; RR 1.04, 95% CI 0.96 to 1.13, P = 0.31; low quality of evidence. risk of death on induction therapy: two studies, 964 patients; RR 0.75, 95% CI 0.50 to 1.13, P = 0.17; moderate quality of evidence). Neither study reported the risks of relapse and grade 3/4 cardiotoxicity. One trial showed that IDA reduced the risk of grade 3/4 mucositis. Neither study reported on QoL. AUTHORS' CONCLUSIONS: Compared with DNR in induction therapy of newly diagnosed AML, IDA prolongs OS and DFS, increases CR rate and reduces relapse rate, although increases the risks of death on induction therapy and grade 3/4 mucositis. The currently available evidence does not show any difference between IDA and MIT used in induction therapy of newly diagnosed AML. There is insufficient evidence regarding IDA versus DOX and IDA versus ZRB to make final conclusions. Additionally, there is no evidence for difference on the effect of IDA compared with DNR, MIT, DOX or ZRB on QoL.

The novel HLA-C*03:652 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-C*03:652 differs from the HLA-C*03:04:01:01 by one nucleotide in exon 3.

Combination of Anti-thymocyte Globulin with Post-transplant Cyclophosphamide for GVHD Prophylaxis in Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-analysis.

A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for graft-versus-host disease (GVHD) prevention was developed. This study aims to perform a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haploidentical hematopoietic stem cell transplantation. Meta-analysis was conducted with Review Manager version 5.4; pooled risk ratios (RRs) and hazard ratios (HRs) were calculated for dichotomous data and time-to-event data, respectively. A fixed-effects model was used if there was no significant heterogeneity. Literature search and study selection identified 14 eligible studies, including both randomized controlled trial and retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grades II-IV acute GVHD compared with ATG (RR 0.52; 95% CI: 0.41-0.65; P < .00001) and PTCy (RR 0.53; 95% CI: 0.34-0.83; P = .005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly better overall survival and GVHD-free/relapse-free survival than ATG and PTCy. Future research is required to further establish the benefits of ATG/PTCy and determine the optimal dosage adjustment strategies. BACKGROUND: Haploidentical stem cell transplantation (haplo-HSCT) is associated with higher incidences of graft-versus-host disease (GVHD). A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for GVHD prevention has been developed, but its benefits and risks remain unclear. OBJECTIVE: This study aims to performs a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haplo-HSCT. STUDY DESIGN: Literature search was performed in databases including Ovid Medline, Embase, Cochrane Library and China Biology Medicine (CBM). Two investigators independently screened eligible studies and extracted data. Meta-analysis was conducted with Review Manager version 5.4; pooled hazard ratios (HRs) for time-to-event outcomes were obtained using a generic inverse-variance method, and pooled risk ratios (RRs) for dichotomous data were obtained using the Mantel-Haenszel method. A fixed-effects model was adopted if there was no significant heterogeneity. The primary outcome is incidence of acute GVHD. RESULTS: Literature search and study selection identified 14 eligible studies, including both 1 randomized controlled trial and 13 retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grades II-IV acute GVHD compared with ATG (RR 0.52; 95% CI: 0.41-0.65; P < .00001) and PTCy (RR 0.53; 95% CI: 0.34-0.83; P = .005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly lower risk of grades III-IV acute GVHD (RR 0.33; 95% CI: 0.23-0.49; P < .00001) and chronic GVHD (RR 0.65; 95% CI: 0.51-0.81; P = .0002) in comparison with ATG. Further analyses suggest that ATG/PTCy is associated with significantly better overall survival and GVHD-free/relapse-free survival than ATG and PTCy, but the risks of cytomegalovirus (RR 1.42; 95% CI: 1.03-1.95; P = .03) and Epstein Barr Virus (RR 3.17; 95% CI: 1.61-6.23; P = .0008) reactivation are higher when compared with PTCy. CONCLUSIONS: Our results suggest that the combination of ATG with PTCy for GVHD prevention in haplo-HSCT is associated with improved efficacy but higher risk of infection. Future research is required to further establish the benefits and risks of ATG/PTCy and determine the optimal dosage adjustment strategies.

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.

Albumin-to-fibrinogen ratio is an independent prognostic parameter in de novo non-M3 acute myeloid leukemia.

Inflammation and nutrition related proteins participate in the development of acute myeloid leukemia (AML). It has been reported that the albumin-to-fibrinogen ratio (AFR) could serve as a prognostic indicator in patients with malignancy, but the precise relevance of AML is unclear. This study aimed to evaluate the effect of AFR on survival prognosis in patients with AML. We analyzed 227 patients newly diagnosed with non-M3 AML. AFR was calculated as albumin divided by fibrinogen. Based on the cutoff point from X-tile program, patients were divided into AFR-high (38.8%) and AFR-low (61.2%) groups. AFR-low group showed a poorer complete remission rate (P < 0.001) and median time to relapse (P = 0.026), while the mortality was higher (P = 0.009) than AFR-high ones. According to the log-rank test, AFR-low group had shorter OS (P < 0.001) and DFS (P = 0.034). Multivariate analysis identified AFR, ELN risk, bone marrow transplant, and hemoglobin as independent prognostic variables associated with OS. A visualized nomogram for predicting OS was performed. The C-index (0.75), calibration plots, and decision curve analyses of new model showed better discrimination, calibration, and net benefits than the ELN risk model. The time-dependent receiver operating characteristic (ROC) curve of 1-, 2-, and 3-year also functioned well (AUC, 0.81, 0.93 and 0.90, respectively). Our study provided a comprehensive view of AFR which could be an independent prognostic indicator in AML patients. The prognostic model utilized readily available information from ordinary clinical practice to improve predictive performance, identify risks, and assist in therapeutic decision-making.

Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis.

The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation.

Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials.

Objective: Steroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens. Methods: Literature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method. Results: Eight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy. Conclusions: Adding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.

Effects of donor-specific antibodies on engraftment and long-term survival after allogeneic hematopoietic stem cell transplantation-A systematic review and meta-analysis.

The presence of donor-specific antibodies (DSAs) have been reported to be associated with an increased risk of primary graft failure following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its effects on the time to engraftment and long-term outcomes remain unclear. We performed a systematic review and meta-analysis of studies investigating the impact of DSAs on engraftment and long-term survival of patients undergoing allo-HSCT. We systematically searched PubMed, Embase, the Cochrane Library, and CBM. Data were analyzed using RevMan5.4. Pooled hazard ratio (HR), standard mean difference (SMD) or odds ratio (OR) and corresponding 95% confidence interval (CI) are calculated for time-to-event data, continuous data, discontinuous data respectively. 17 eligible studies were included, involving 2169 patients main receiving haploidentical SCT (haplo-SCT) or umbilical cord blood transplantation (UCBT). Meta-analysis showed that DSAs-positive patients are associated with significantly higher risk of GF(OR = 12.87, 95%CI, 6.45-25.70; P < 0.00001; OR = 4.76, 95%CI, 2.88-7.87), poorer neutrophil engraftment (HR = 2.20, 95%CI, 1.02-4.73; P = 0.04; HR = 1.83, 95%CI, 1.46-2.30; P < 0.00001), worse OS (HR = 3.19, 95%CI, 1.85-5.50; P < 0.0001; HR = 1.68, 95%CI, 1.04-2.71; P = 0.03), and inferior PFS (HR = 4.25, 95%CI, 1.59-11.40; P = 0.004; HR = 4.83, 95%CI, 1.65-14.12; P = 0.004) in haplo-SCT and UCBT, respectively.

Gene mutation analysis using next-generation sequencing and its clinical significance in patients with myeloid neoplasm: A multi-center study from China.

BACKGROUND: Myeloid neoplasms (MN) tend to relapse and deteriorate. Exploring the genomic mutation landscape of MN using next-generation sequencing (NGS) is a great measure to clarify the mechanism of oncogenesis and progression of MN. METHODS: This multicenter retrospective study investigated 303 patients with MN using NGS from 2019 to 2021. The characteristics of the mutation landscape in the MN subgroups and the clinical value of gene variants were analyzed. RESULTS: At least one mutation was detected in 88.11% of the patients (267/303). TET2 was the most common mutation in the cohort, followed by GATA2, ASXL1, FLT3, DNMT3A, and TP53. Among patients with myeloid leukemia (ML), multivariate analysis showed that patients aged ≥60 years had lower overall survival (OS, p = 0.004). Further analysis showed TET2, NPM1, SRSF2, and IDH1 gene mutations, and epigenetic genes (p < 0.050) presented significantly higher frequency in older patients. In patients with myelodysplastic syndrome (MDS) and myelodysplastic neoplasms (MPN), univariate analysis showed that BCORL1 had a significant impact on OS (p = 0.040); however, in multivariate analysis, there were no factors significantly associated with OS. Differential analysis of genetic mutations showed FLT3, TP53, MUC16, SRSF2, and KDM5A mutated more frequently (p < 0.050) in secondary acute myeloid leukemia (s-AML) than in MDS and MPN. TP53, U2AF1, SRSF2, and KDM5A were mutated more frequently (p < 0.050) in s-AML than in primary AML. KDM5A was observed to be restricted to patients with s-AML in this study, and only co-occurred with MUC16 and TP53 (2/2, 100%). Another mutation was MUC16, and its co-occurrence pattern differed between s-AML and AML. MUC16 mutations co-occurred with KDM5A and TP53 in 66.7% (2/3) of patients with s-AML and co-occurred with CEBPA in 100% (4/4) of patients with AML. CONCLUSIONS: Our results demonstrate different genomic mutation patterns in the MN subgroups and highlight the clinical value of genetic variants.

Targeting PI4KA sensitizes refractory leukemia to chemotherapy by modulating the ERK/AMPK/OXPHOS axis.

Background: The emergence of chemoresistance in leukemia markedly impedes chemotherapeutic efficacy and dictates poor prognosis. Recent evidence has revealed that phosphatidylinositol 4 kinase-IIIα (PI4KA) plays a critical role in tumorigenesis. However, the molecular mechanisms of PI4KA-regulated chemoresistance and leukemogenesis remain largely unknown. Methods: Liquid chromatography-mass spectrometry (LC-MS), patient samples and leukemia xenograft mouse models were used to investigate whether PI4KA was an effective target to overcome chemoresistance in leukemia. Enzyme-linked immunosorbent assay (ELISA) and molecular mechanics/generalized born surface area (MM/GBSA) method were employed to identify cepharanthine (CEP) as a novel PI4KA inhibitor. Results: High expression of PI4KA was observed in drug-resistant leukemia cells or in relapsed leukemia patients, which was correlated with poor overall survival. Depletion of PI4KA sensitized drug-resistant leukemia cells to chemotherapeutic drugs in vitro and in vivo by regulating ERK/AMPK/OXPHOS axis. We also identified cepharanthine (CEP) as a novel PI4KA inhibitor, which could undermine the stability of the PI4KA/TTC7/FAM126 complex, enhancing the sensitivity of drug-resistant leukemia cells to chemotherapeutic drugs in vitro and in vivo. Conclusions: Our study underscored the potential of therapeutic targeting of PI4KA to overcome chemoresistance in leukemia. A combination of the PI4KA inhibitor with classic chemotherapeutic agents could represent a novel therapeutic strategy for the treatment of refractory leukemia.

COVID-19 metabolism: Mechanisms and therapeutic targets.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dysregulates antiviral signaling, immune response, and cell metabolism in human body. Viral genome and proteins hijack host metabolic network to support viral biogenesis and propagation. However, the regulatory mechanism of SARS-CoV-2-induced metabolic dysfunction has not been elucidated until recently. Multiomic studies of coronavirus disease 2019 (COVID-19) revealed an intensive interaction between host metabolic regulators and viral proteins. SARS-CoV-2 deregulated cellular metabolism in blood, intestine, liver, pancreas, fat, and immune cells. Host metabolism supported almost every stage of viral lifecycle. Strikingly, viral proteins were found to interact with metabolic enzymes in different cellular compartments. Biochemical and genetic assays also identified key regulatory nodes and metabolic dependencies of viral replication. Of note, cholesterol metabolism, lipid metabolism, and glucose metabolism are broadly involved in viral lifecycle. Here, we summarized the current understanding of the hallmarks of COVID-19 metabolism. SARS-CoV-2 infection remodels host cell metabolism, which in turn modulates viral biogenesis and replication. Remodeling of host metabolism creates metabolic vulnerability of SARS-CoV-2 replication, which could be explored to uncover new therapeutic targets. The efficacy of metabolic inhibitors against COVID-19 is under investigation in several clinical trials. Ultimately, the knowledge of SARS-CoV-2-induced metabolic reprogramming would accelerate drug repurposing or screening to combat the COVID-19 pandemic.

Efficacy of hematopoietic stem cell mobilization regimens in patients with hematological malignancies: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Efficient mobilization of hematopoietic stem cells (HSCs) from bone marrow niche into circulation is the key to successful collection and transplantation in patients with hematological malignancies. The efficacy of various HSCs mobilization regimens has been widely investigated, but the results are inconsistent. METHODS: We performed comprehensive databases searching for eligible randomized controlled trials (RCTs) that comparing the efficacy of HSCs mobilization regimens in patients with hematological malignancies. Bayesian network meta-analyses were performed with WinBUGS. Standard dose of granulocyte colony-stimulating factor (G-CSF SD) was chosen as the common comparator. Estimates of relative treatment effects for other regimens were reported as mean differences (MD) or odds ratio (OR) with associated 95% credibility interval (95% CrI). The surface under the cumulative ranking curve (SUCRA) were obtained to present rank probabilities of all included regimens. RESULTS: Databases searching and study selection identified 44 eligible RCTs, of which the mobilization results are summarized. Then we compared the efficacy of mobilization regimens separately for patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) by including 13 eligible trials for network meta-analysis, involving 638 patients with MM and 592 patients with NHL. For patients with MM, data are pooled from 8 trials for 6 regimens, including G-CSF in standard dose (SD) or reduced dose (RD) combined with cyclophosphamide (CY), intermediate-dose cytarabine (ID-AraC) or plerixafor. The results show that compared with G-CSF SD alone, 3 regimens including ID-AraC + G-CSF SD (MD 14.29, 95% CrI 9.99-18.53; SUCRA 1.00), G-CSF SD + Plerixafor SD (MD 4.15, 95% CrI 2.92-5.39; SUCRA 0.80), and CY + G-CSF RD (MD 1.18, 95% CrI 0.29-2.07; SUCRA 0.60) are associated with significantly increased total number of collected CD34+ cells (× 106/kg), among which ID-AraC + G-CSF SD ranked first with a probability of being best regimen of 100%. Moreover, ID-AraC + G-CSF SD and G-CSF SD + Plerixafor SD are associated with significantly higher successful rate of achieving optimal target (collecting ≥ 4-6 × 106 CD34+ cells/kg). For patients with NHL, data are pooled from 5 trials for 4 regimens, the results show that compared with G-CSF SD alone, G-CSF SD + Plerixafor SD (MD 3.62, 95% CrI 2.86-4.38; SUCRA 0.81) and G-CSF SD plus the new CXC chemokine receptor-4 (CXCR-4) antagonist YF-H-2015005 (MD 3.43, 95% CrI 2.51-4.35; SUCRA 0.69) are associated with significantly higher number of total CD34+ cells collected. These 2 regimens are also associated with significantly higher successful rate of achieving optimal target. There are no significant differences in rate of achieving optimal target between G-CSF SD + Plerixafor SD and G-CSF + YF-H-2015005. CONCLUSIONS: In conclusion, ID-AraC plus G-CSF is associated with the highest probability of being best mobilization regimen in patients with MM. For patients with NHL, G-CSF in combination with plerixafor or YF-H-2015005 showed similar improvements in HSCs mobilization efficacy. The relative effects of other chemotherapy-based mobilization regimens still require to be determined with further investigations.

Decoding the Mechanism of Shen Qi Sha Bai Decoction in Treating Acute Myeloid Leukemia Based on Network Pharmacology and Molecular Docking.

Traditional Chinese Medicine (TCM) has been shown to be efficacious in treating leukemia for thousands of years. It has been shown that Shen Qi Sha Bai Decoction (SQSBD) has been extensively used in the treatment of acute myeloid leukemia (AML). However, the mechanism of SQSBD in treating AML remains unclear. In this study, we employed network pharmacology to analyze the potential active components and elucidate molecular mechanism of SQSBD in treating AML. A total of 268 active components were identified from SQSBD, among which 9 key components (Quercetin, luteolin, kaempferol, licochalcone A, formononetin, wogonin, ß-sitosterol, oroxylin A, naringenin, and baicalein) were hit by the 6 hub targets (CDK1, MAPK1, JUN, PCNA, HSB1, STAT3) associated with leukemia. Molecular docking showed that two core active components, quercetin and licochalcone A, exhibited the highest component-like properties (DL), and could bind well to CDK1 and MAPK1 protein. The experimental validation of these two components showed that quercetin inhibited cell growth through CDK1 dephosphorylation-mediated cell cycle arrest at G2/M phase in human AML U937 and HL60 cells, and licochalcone A induced cell differentiation in these leukemia cells via activation of MAPK1 and upregulation of CD11b. All these results indicate that SQSBD is effective in the treatment of AML, and quercetin and licochalcone A are the major candidate compounds for AML treatment.

Efficacy and safety of mesenchymal stem cells co-infusion in allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is life-saving for severe hematological conditions. However, its outcomes need further improvement, and co-infusion of mesenchymal stem cells (MSCs) may show promise. A growing body of research on this subject exists, while the results of different trials are conflicting. A systematic review and meta-analysis is needed to appraise the real efficacy and safety of MSC co-transplantation in allo-HSCT. METHODS: Studies comparing MSC co-transplantation in allo-HSCT with allo-HSCT alone were searched in six medical databases from inception to June 10, 2020. The primary outcomes were engraftment and graft-versus-host disease (aGVHD and cGVHD, respectively). Other outcomes included overall survival (OS), relapse rate (RR), non-relapse mortality (NRM), and immune reconstitution. Information was independently extracted by two investigators. Methodological quality was assessed using the Cochrane Collaboration tool. Meta-analysis was performed using RevMan 5.4. RESULTS: Six randomized controlled trials (RCTs) and 13 non-randomized controlled trials (nRCTs) were included. MSC co-infusion resulted in shorter times to neutrophil engraftment (RCTs: standardized mean difference (SMD) - 1.20, p = 0.04; nRCTs: SMD - 0.54, p = 0.04) and platelet engraftment (RCTs: SMD - 0.60, p = 0.04; nRCTs: SMD - 0.70, p = 0.01), a lower risk of cGVHD (RCTs: risk ratio (RR) 0.53, p = 0.01; nRCTs: RR 0.50, p <  0.01), and a slightly positive trend towards reducing the risk of aGVHD and NRM, without affecting RR and OS. Subgroup analyses revealed that when MSCs were co-transplanted, children and adolescents, and patients receiving human leukocyte antigen (HLA)-nonidentical HSCT showed improvements in engraftment and incidence of GVHD and NRM; adults and patients who received HLA-identical HSCT had lower cGVHD; patients with malignancies exhibited improvements in GVHD and NRM incidence; and patients with non-malignancies experienced accelerated engraftment. Notably, a reduced OS was observed in patients with hematological malignancies undergoing HLA-identical HSCT. CONCLUSION: MSC co-infusion generally improved engraftment and reduced cGVHD, without increasing mortality or relapse. Regarding aGVHD and NRM, the effects of MSCs were not quite significant. Specifically, our data support the utilization of MSC co-transplantation in children and young individuals with HLA-nonidentical HSCT, but not in adult patients with hematological malignancies undergoing HLA-identical HSCT.