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Palmitic acid reduces the methylation of the FOXO1 promoter to suppress the development of diffuse large b-cell lymphoma via modulating the miR-429/DNMT3A axis

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Chinese Journal of Natural Medicines 2024年第6期22卷 554-567页

作者： LI Weiming GAO Ming XUE Weili LI Xiaoli CHANG Yu ZHANG Kaixin WEN Chenyu ZHANG Mingzhi Department of Oncology Henan University of Traditional Chinese MedicineZhengzhou 450000China Department of Oncology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450000China

diffuse large b-cell lymphoma(DLbCL)is characterized by significant treatment resistance.Palmitic acid(PA)has shown promising antitumor properties.This study aims to elucidate the molecular mechanisms by which PA influences DLbCL progression.We quantified the expression levels of microRNAs(miRNAs),Forkhead box protein O1(FOXO1),and DNA methyltransferase 3A(DNMT3A)in both untreated and PA-treated DLbCL tumors and cell lines.Assessments were made of cell viability,apoptosis,and autophagy-related protein expression following PA administration.Interaction analyses among miR-429,DNMT3A,and FOXO1 were conducted using luciferase reporter assays and methylation-specific(MSP)Polymerase chain reaction(PCR).After transfecting the miR-429 inhibitor,negative control(NC)inhibitor,shRNA against DNMT3A(sh-DNMT3A),shRNA negative control(sh-NC),over-expression vector for DNMT3A(oe-DNMT3A),or overexpression negative control(oe-NC),we evaluated the effects of miR-429 and DNMT3A on cell viability,mortality,and autophagy-related protein expression in PA-treated DLbCL cell lines.The efficacy of PA was also tested in vivo using DLbCL tumor-bearing mouse models.MiR-429 and FOXO1 expression levels were downregulated,whereas DNMT3A was upregulated in DLbCL compared to the control group.PA treatment was associated with enhanced autophagy,mediated by the upregulation of miR-429 and downregulation of DNMT3A.The luciferase reporter assay and MSP confirmed that miR-429 directly inhibits DNMT3A,thereby reducing FOXO1 methylation.Subsequent experiments demonstrated that PA promotes autophagy and inhibits DLbCL progression by upregulating miR-429 and modulating the DNMT3A/FOXO1 axis.In vivo PA signific-antly reduced the growth of xenografted tumors through its regulatory impact on the miR-429/DNMT3A/FOXO1 axis.Palmitic acid may modulate autophagy and inhibit DLbCL progression by targeting the miR-429/DNMT3A/FOXO1 signaling pathway,suggesting a novel therapeutic target for DLbCL management.

关键词： Palmitic acid diffuse large b-cell lymphoma MiR-429 DNMT3A FOXO1 Autophagy

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Prognostic value of bCL2 and TP53 genetic alterations for diffuse large b-cell lymphoma patients treated with R-CHOP

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Cancer biology & Medicine 2022年第6期19卷 893-909页

作者： Yan Qin Haizhu Chen Peng Liu Changgong Zhang Jianliang Yang Lin Gui Xiaohui He Liqiang Zhou Shengyu Zhou Shiyu Jiang Hongxin Jiang Yuankai Shi Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted DrugsBeijing 100021China Department of Medical Oncology Suzhou Municipal HospitalAffiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou 215001China

Objective:Limited data about the prognostic significance of bCL2 mutations and bCL2 copy number variations in diffuse large b-cell lymphoma(DLbCL)are available.This study aimed to comprehensively describe bCL2 genetic alterations in DLbCL patients,and examine correlation of bCL2,TP53 and other genetic alterations with outcomes in patients treated with R-CHOP.Methods:Probe capture-based high-resolution sequencing was performed on 191 patients diagnosed with de novo DLbCL.MYC,bCL2,and bCL6 protein expressions were detected by immunohistochemistry.Results:The presence of bCL2 alterations significantly correlated with poor progression-free survival(PFS)(5-year PFS:13.7%vs.40.8%;P=0.003)and overall survival(OS)(5-year OS:34.0%vs.70.9%;P=0.036).Importantly,patients who harbored bCL2 gain/amplifications(bCL2GA/AMP)also had a remarkably inferior 5-year PFS(11.1%vs.38.3%;PbCL2 mutations nor bCL2 translocations were significantly prognostic for survival.Multivariable analyses showed that the presence of bCL2 alterations,especially bCL2GA/AMP,TP53 mutations,and International Prognostic Index(IPI)were significantly associated with inferior PFS and OS.Novel prognostic models for OS were constructed based on 3 risk factors,including bCL2 alterations(Model 1)or bCL2GA/AMP(Model 2),TP53 mutations,and IPI,to stratify patients into 4 risk groups with different survival outcomes.Conclusions:This study showed that DLbCL patients treated with R-CHOP,bCL2 alterations,especially bCL2GA/AMP and TP53 mutations were significantly associated with inferior outcomes,which were independent of the IPI.The novel prognostic models we proposed predicted outcomes for DLbCL patients treated with R-CHOP,but further validation of the prognostic models is still warranted.

关键词： bCL2 TP53 genetic alterations diffuse large b-cell lymphoma prognosis

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Chidamide and sintilimab combination in diffuse large b-cell lymphoma progressing after chimeric antigen receptor T therapy

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World Journal of Clinical Cases 2022年第19期10卷 6555-6562页

作者： Yuan-Yuan Hao Pan-Pan Chen Xiang-Gui Yuan Ai-Qi Zhao Yun Liang Hui Liu Wen-bin Qian Department of Hematology The Second Affiliated Hospital of Zhejiang University School of MedicineHangzhou 310009Zhejiang ProvinceChina

bACKGROUND diffuse large b-cell lymphoma(DLbCL)is curable with first-line chemoimmunotherapy but patients with relapsed/refractory(R/R)DLbCL still face a poor prognosis.For patients with R/R DLbCL,the complete response rate to traditional next-line therapy is only 7%and the median overall survival is 6.3 mo.Recently,CD19-targeting chimeric antigen receptor T cells(CAR-T)have shown promise in clinical trials.However,approximately 50%of patients treated with CAR-T cells ultimately progress and few salvage therapies are effective.CASE SUMMARY Here,we report on 7 patients with R/R DLbCL whose disease progressed after CAR-T infusion.They received a PD-1 inhibitor(sintilimab)and a histone deacetylase inhibitor(chidamide).Five of the 7 patients tolerated the treatment without any serious adverse events.Two patients discontinued the treatment due to lung infection and rash.At the 20-mo follow-up,the median overall survival of these 7 patients was 6 mo.Of note,there were 2 complete response rates(CRs)and 2 partial response rates(PRs)during this novel therapy,with an overall response rate(ORR)of 57.1%,and one patient had a durable CR that lasted at least 20 mo.CONCLUSION In conclusion,chidamide combined with sintilimab may be a choice for DLbCL patients progressing after CD19-targeting CAR-T therapy.

关键词： Chimeric antigen receptor T cell therapy diffuse large b-cell lymphoma Immunotherapy PD-1 inhibitor Histone deacetylase inhibitor Case report

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PHOSPHO1 Serves as a Key Metabolism-Related biomarker in the Tumorigenesis of diffuse large b-cell lymphoma

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Current Medical Science 2022年第4期42卷 754-768页

作者： Tian-rui CHEN Huang-ming CAO Yin WU Jiang-tao XIE Hai-feng LAN Li-na JIN Department of Medicine Shanghai Di An Medical Laboratory Co.LtdShanghai 200433China Department of Orthopedic Oncology Changzheng HospitalNaval Medical UniversityShanghai 200003China Department of Oncology Shanghai East HospitalTongji University School of MedicineShanghai 200120China Department of Hematology Shanghai East HospitalTongji University School of MedicineShanghai 200120China Department of Hematology Myeloma&Lymphoma Center Changzheng HospitalNaval Medical UniversityShanghai 200003China

Objective:diffuse large b-cell lymphoma(DLbCL)is an aggressive type of non-Hodgkin lymphoma.Due to its genetic heterogeneity and abnormal metabolism,many DLbCL patients have a poor prognosis.This study investigated the key metabolism-related genes and potential mechanisms.Methods:Differentially expressed genes,differentially expressed transcription factors(TFs),and differentially expressed metabolism-related genes(DEMRGs)of glucose and lipid metabolic processes were identified using the edgeR package.Key DEMRGs were screened by Lasso regression,and a prediction model was constructed.The cell type identification by estimating relative subsets of RNA transcripts algorithm was utilized to assess the fraction of immune cells,and Gene Set Enrichment Analysis was used to determine immune-related pathways.A regulatory network was constructed with significant co-expression interactions among TFs,DEMRGs,immune cells/pathways,and hallmark pathways.Results:A total of 1551 DEMRGs were identified.A prognostic model with a high applicability(area under the curve=0.921)was constructed with 13 DEMRGs.Tumorigenesis of DLbCL was highly related to the neutrophil count.Four DEMRGs(PRXL2Ab,CCN1,DECR2 and PHOSPHO1)with 32 TF-DEMRG,36 DEMRG-pathway,14 DEMRG-immune-cell,9 DEMRG-immune-gene-set,and 67 DEMRG-protein-chip interactions were used to construct the regulatory network.Conclusion:We provided a prognostic prediction model based on 13 DEMRGs for DLbCL.We found that phosphatase,orphan 1(PHOSPHO1)is positively regulated by regulatory factor X5(RFX5)and mediates MYC proto-oncogene(MYC)targeting the V2 pathway and neutrophils.

关键词： diffuse large b-cell lymphoma metabolism-related gene immune microenvironment regulatory network PHOSPHO1

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Positron emission tomography-adapted therapy in low-risk diffuse large b-cell lymphoma:results of a randomized,phase Ⅲ,non-inferiority trial

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Cancer Communications 2023年第8期43卷 896-908页

作者： Qing Shi Yang He Hong-Mei Yi Rong-Ji Mu Xu-Feng Jiang Di Fu Lei Dong Wei Qin Peng-Peng Xu Shu Cheng Qi Song Sai-Juan Chen Li Wang Wei-Li Zhao State Key Laboratory of Medical Genomics National Research Center for Translational Medicine at ShanghaiShanghai Institute of HematologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Department of Pathology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Clinical Research Institute Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Department of Nuclear Medicine Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Department of Radiology Ruijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiP.R.China Laboratory of Molecular Pathology Pole de Recherches Sino-Francis en Science du Vivant et GénomiqueShanghaiChina

background:The current standard of care for non-bulky diffuse large b-cell lymphoma(DLbCL)patients with an International Prognostic Index(IPI)of 0 is four cycles of rituximab plus cyclophosphamide,doxorubicin,vincristine and prednisone(R-CHOP)but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non-bulky DLbCL patients with an IPI of 1 remains unclear.This study compared four cycles versus six cycles of chemotherapy in non-bulky low-risk DLbCL patients with negative interim positron emission tomography with computed tomography(PET-CT,Deauville 1-3),irrespective of age and other IPI risk factors(IPI 0-1).Methods:This was an open-label,randomized,phaseⅢ,non-inferiority trial.Patients aged 14-75 years with newly diagnosed low-risk DLbCL,according to IPI,achieving PET-CT confirmed complete response(CR)after four cycles of R-CHOPwere randomized(1:1)between four cycles of rituximab(4R-CHOP+4R arm)or two cycles of R-CHOP plus two cycles of rituximab(6R-CHOP+2R arm).The primary endpoint was 2-year progression-free survival(PFS),conducted in the intention-to-treat population.Safety was assessed in patients with at least one cycle of assigned treatment.The non-inferiority margin was-8%.Results:A total of 287 patients were included in the intention-to-treat analysis,the median follow-up was 47.3 months,and the 2-year PFS rate was 95%(95%confidence interval[CI],92%to 99%)and 94%(95%CI,91%to 98%)for the 4R-CHOP+4R and 6R-CHOP+2R arm.The absolute difference in 2-year PFS between the two arms was 1%(95%CI,-5%to 7%),supporting the non-inferiority of 4R-CHOP+4R.Grade 3-4 neutropenia was lower in the last four cycles of rituximab alone in the 4R-CHOP+4R arm(16.7%versus 76.9%),with decreased risk of febrile neutropenia(0.0%versus 8.4%)and infection(2.1%versus 14.0%).Conclusions:For newly diagnosed low-risk DLbCL patients,interim PET-CT after four cycles of R-CHOP was effective in identifying patients with Deauville 1-3 who would have a good response and Deauville 4-5 patients who might

关键词： diffuse large b-cell lymphoma low-risk positron emission tomography randomized phaseⅢtrial

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T-cell immunoglobulin mucin molecule-3, transformation growth factor β, and chemokine-12 and the prognostic status of diffuse large b-cell lymphoma

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World Journal of Clinical Cases 2022年第32期10卷 11804-11811页

作者： Hao Wu Hui-Cong Sun Gui-Fang Ouyang Department of Hematology Ningbo First HospitalNingbo Clinical Research Center for Hematologic MalignanciesNingbo 315010Zhejiang ProvinceChina Department of Adult Internal Medicine Ningbo Women and Children's HospitalNingbo 315012Zhejiang ProvinceChina

bACKGROUND The effects of T-cell immunoglobulin mucin molecule-3(Tim-3),transforming growth factor β(TGF-β),and chemokine-12(CXCL12) expression on the prognosis of patients with diffuse large b-cell lymphoma(DLbCL) have not been elucidated.AIM To examine the correlation between Tim-3,TGF-β and CXCL12 expression and DLbCL prognosis.METHODS Lymph node tissues of 97 patients with DLbCL and 93 normal-response hyperplastic lymph node tissues treated from January 2017 to May 2019 were selected as the DLbCL and control groups,respectively.The expression of Tim-3,TGF-β,and CXCL12 was detected immunohistochemically.Patients were followed up for 3 years,and progression-free survival was recorded.Cox mult-ifactorial analysis was performed to analyze the risk factors for poor prognosis.RESULTS The positive expression rates of Tim-3,TGF-β,and CXCL12 were higher in DLbCL tissues than in non-cancerous(control) tissues(P bCL was 67.01%(65/97).Univariate analysis revealed that clinical stage,bone marrow infiltration,International Prognostic Index(IPI) score,Tim-3 positivity,TGF-β positivity,and CXCL12 positivity were associated with poor prognosis(P bone marrow infiltration,mediate-to-high-risk IPI scores,Tim-3 positivity,TGF-β positivity,and CXCL12 positivity were independent risk factors affecting prognosis(P bCL tissues exhibit high positive expression of Tim-3,TGF-β,and CXCL12,and a high expression of all three indicates a poor prognosis.

关键词： T-cell immunoglobulin mucin molecule-3 Transforming growth factorβ Chemokine-12 diffuse large b-cell lymphoma

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Effect of T-regulatory cells and interleukin-35, interleukin-10, and transforming growth factor-beta on diffuse large b-cell lymphoma

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World Journal of Clinical Cases 2023年第29期11卷 7075-7081页

作者： Hao Wu Hui-Cong Sun Gui-Fang Ouyang Department of Hematology The First Affiliated Hospital of Ningbo UniversityNingbo 315010Zhejiang ProvinceChina Adult Internal Medicine Ningbo Women and Children's HospitalNingbo 315012Zhejiang ProvinceChina

bACKGROUND diffuse large b-cell lymphoma(DLbCL)is an aggressive non-Hodgkin lymphoma that affects b lymphocytes.It can develop in the lymph nodes and can be localized or generalized.Despite DLbCL being considered potentially curable,little research has been conducted on the relationship between the body's immune response and DLbCL.AIM To study the expression and significance of T-regulatory cells(Tregs)interleukin(IL)-35,IL-10,and transforming growth factor-beta(TGF-β)in DLbCL.METHODS Data from 82 patients with DLbCL who were initially admitted to The First Affiliated Hospital of Ningbo University(Zhejiang Province,China)between January 2017 and June 2022 and treated with standard first-line regimens were reviewed.Three patients were lost to follow-up;thus,79 patients were included in the statistical analysis and then divided into three groups according to the evaluation of clinical efficacy:Incipient(new-onset and treatment-naïve),effectively treated,and relapsed-refractory.Thirty healthy individuals were included in the control group.The expression of peripheral blood T lymphocytes and their associated factors IL-35,IL-10,and TGF-βin the four groups were observed.RESULTS In contrast to the successfully treated and normal control groups,both the incipient and relapse-refractory groups exhibited greater proportions of CD4-positive(+)Tregs(Pbstantially between the groups.Serum levels of IL-35 and IL-10 in the incipient and relapsed-refractory groups were higher than those in the effectively treated and normal control groups(Pbetween the groups(P>0.05).The correlation between IL-35 and IL-10 concentrations was significantly positive,with a correlation coefficient of 0.531(Pbetween IL-35 and TGF-βconcentration was significantly positive,with a correlation coefficient of 0.375(Pbetween IL-10 and TGF-βconcentration was signif

关键词： diffuse large b-cell lymphoma T-regulatory cells Interleukin-35 Interleukin-10 Transforming growth factorbeta Immune response

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Rituximab combined with bruton tyrosine kinase inhibitor to treat elderly diffuse large b-cell lymphoma patients: Two case reports

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World Journal of Clinical Cases 2023年第29期11卷 7170-7178页

作者： Cang-Jian Zhang Min-Lei Zhao Department of Hematology Lishui Municipal Central HospitalLishui 323000Zhejiang ProvinceChina

bACKGROUND diffuse large b-cell lymphoma(DLbCL)is a common aggressive non-Hodgkin's lymphoma(NHL),accounting for 30%-40%of adult NHLs.This report aims to explore the efficacy and safety of rituximab combined with bruton tyrosine kinase inhibitors(bTKis)in the treatment of elderly patients with DLbCL.CASE SUMMARY The clinical data of two elderly patients with DLbCL who received rituximab combined with bTKi in our hospital were retrospectively analyzed,and the literature was reviewed.The patients were treated with chemotherapy using the R-miniCHOP regimen for two courses.Then,they received rituximab in combination with bTKi.CONCLUSION The treatment experience in these cases demonstrates the potential efficacy of rituximab combined with bTKi to treat elderly DLbCL patients,thus providing a new treatment strategy.

关键词： diffuse large b-cell lymphoma Rituximab bruton tyrosine kinase inhibitors Elderly patients Case report

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diffuse large b-cell lymphoma successfully treated with amplified natural killer therapy alone: A case report

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World Journal of Clinical Cases 2023年第30期11卷 7432-7439页

作者： Kenjiro Nagai Syo Nagai Yuji Okubo Keisuke Teshigawara Department of Internal Medicine Medical Corporation Ebino Centro ClinicEbino 889-4304Japan Department of Internal Medicine Higashinotoin ClinicKyoto 604-8175Japan

bACKGROUND The prognosis of patients with advanced diffuse large b-cell lymphoma(DLbCL)is poor,with a 5-year survival rate of approximately 50%.The mainstay of treatment is multidrug combination chemotherapy,which has been associated with serious side effects.Amplified natural killer(ANK)cell therapy amplifies and activates natural killer(NK)cells to attack only malignant tumors.As ANK cells attack programmed death ligand 1(PD-L1)-positive tumor cells,ANK therapy is considered effective against adult T-cell lymphoma and malignant lymphoma.CASE SUMMARY Herein,we report a case of an older patient with advanced DLbCL who was successfully treated with ANK immunotherapy.A 91-year-old female visited our hospital with sudden swelling of the right axillary lymph node in April 2022.The patient was diagnosed with stage II disease,given the absence of splenic involvement or contralateral lymphadenopathy.ANK therapy was administered.Six rounds of lymphocyte sampling were performed on July 28,2022.To reduce the occurrence of side effects,the six samples were diluted by half to obtain 12 samples.Cultured NK cells were administered twice weekly.The treatment efficacy was evaluated by performing computed tomography and serological tests every 1 or 2 mo.The treatment suppressed lesion growth,and the antitumor effect persisted for several months.The patient experienced mild side effects.PD-L1 immunostaining was positive,indicating that the treatment was highly effective.CONCLUSION ANK therapy can be used as a first-line treatment for malignant lymphoma;the PD-L1 positivity rate can predict treatment efficacy.

关键词： diffuse large b-cell lymphoma Natural killer cells Immunostaining Hodgkin's lymphoma Older adult Case report

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Coexistence of diffuse large b-cell lymphoma,acute myeloid leukemia,and untreated lymphoplasmacytic lymphoma/waldenström macroglobulinemia in a same patient:A case report

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World Journal of Clinical Cases 2023年第18期11卷 4295-4305页

作者： Liu-bo Zhang Lu Zhang Hong-Lei Xin Yan Wang Hong-Yu bao Qing-Qi Meng Su-Yu Jiang Xue Han Wan-Ru Chen Jian-Ning Wang Xiao-Feng Shi Department of Hematology Second Affiliated Hospital of Nanjing Medical UniversityNanjing 210003Jiangsu ProvinceChina Department of Pathology Second Affiliated Hospital of Nanjing Medical UniversityNanjing 210003Jiangsu ProvinceChina

bACKGROUND The Coexistence of myeloid and lymphoid malignancies is rare.Myeloid leukemia occurs more frequently as a secondary event in patients receiving chemotherapy agents for lymphoid malignancies.Synchronous diagnoses of diffuse large b-cell lymphoma(DLbCL),acute myeloid leukemia(AML),and untreated lymphoplasmacytic lymphoma/Waldenström macroglobulinemia(LPL/WM)in the same patient have not been reported.Here we report one such case.CASE SUMMARY An 89-year-old man had a chest wall mass histopathologically diagnosed as DLbCL.The bone marrow and peripheral blood contained two groups of cells.One group of cells fulfilled the criteria of AML,and the other revealed the features of small b lymphocytic proliferative disorder,which we considered LPL/WM.Multiple chromosomal or genetic changes were detected in bone marrow mononuclear cells,including ATM deletion,CCND1 amplification,mutations of MYD88(L265P)and TP53,WT1 overexpression,and fusion gene of bIRC2-ARAP1,as well as complex chromosomal abnormalities.The patient refused chemotherapy because of old age and died of pneumonia 1 mo after the final diagnosis.CONCLUSION The coexistence of DLbCL,AML,and untreated LPL/WM in the same patient is extremely rare,which probably results from multiple steps of genetic abnormalities.Asymptomatic LPL/WM might have occurred first,then myelodysplastic syndromerelated AML developed,and finally aggressive DLbCL arose.Therefore,medical staff should pay attention to this rare phenomenon to avoid misdiagnoses.

关键词： diffuse large b-cell lymphoma Acute myeloid leukemia Small b lymphocyte proliferative disorder Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia Coexistence Case report

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