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 vario...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.展开更多
BACKGROUND Mantle cell lymphoma(MCL)of the gastrointestinal tract is a rare malignancy,accounting for about 0.2%of malignant colorectal tumors.MCL synchronous with rectal adenocarcinoma is extremely rare.We know of on...BACKGROUND Mantle cell lymphoma(MCL)of the gastrointestinal tract is a rare malignancy,accounting for about 0.2%of malignant colorectal tumors.MCL synchronous with rectal adenocarcinoma is extremely rare.We know of only a few cases reported in the literature.We describe the case of a patient with synchronous rectal adenocarcinoma and intestinal MCL.CASE SUMMARY A 63-year-old man was admitted to our hospital due to abdominal pain and hematochezia over the past month.The patient was diagnosed with middle rectal cancer cT2N0M0 and underwent surgery.However,we found a large tumor in the small intestine during surgery.The patient underwent total mesorectal excision for rectal cancer and resectioning of the ileal segment containing the large mass.Pathology and immunohistochemistry revealed the presence of both rectal adenocarcinoma and pathognomonic MCL stage IIE presenting as multiple lymphomatous polyposis.The patient subsequently underwent RDHAP/RCHOP chemotherapy and was maintained with rituximab.A Positron Emission Tomography and Computed Tomography(PET/CT)scan showed that the disease responded well to treatment without tumor-increased metabolism in the gastrointestinal tract.CONCLUSION Synchronous rectal adenocarcinoma and intestinal MCL presenting as multiple lymphomatous polyposis are extremely rare.MCL is often discovered fortuitously when rectal cancer is diagnosed.The coexistence of these tumors poses treatment challenges.展开更多
AIM: To evaluate the endoscopic manifestations and prognoses of gastrointestinal (GI) mantle cell lymphoma (MCL). METHODS: A database search at the Department of Pathology of Okayama University Graduate School of Medi...AIM: To evaluate the endoscopic manifestations and prognoses of gastrointestinal (GI) mantle cell lymphoma (MCL). METHODS: A database search at the Department of Pathology of Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences revealed 57 MCL patients with GI involvement. Clinical records were available for 35 of the 57 patients from 21 institutions, and those 35 patients were enrolled in this study. We summarized the gross types of endoscopic features, event-free survival (EFS), and overall survival (OS) of those patients.RESULTS: Of the 35 patients, GI involvement in the esophagus, stomach, and duodenum was found in 2 (5.7%), 26 (74.3%), and 12 (34.3%) patients, respectively. Twenty-one of the 35 patients underwent colonoscopy; among them, GI involvement in the ileum, cecum, colon, and rectum was found in 10 (47.6%), 3 (14.3%), 12 (57.1%), and 10 (47.6%), respectively. Various lesions, such as superficial, protruded, fold thickening, or ulcerative, were found in the stomach, whereas multiple lymphomatous polyposis (MLP) was dominant from the duodenum to the rectum. Twelve patients were treated with a hyper-CVAD/MA regimen, and they had better OS (3-year rate, 88.3% vs 46.4%, P < 0.01) and better EFS (3-year rate, 66.7% vs 33.8%, P < 0.05) than the remaining 23 patients who were not treated with this regimen. CONCLUSION: MLP was a representative form of intestinal involvement, whereas a variety of lesions were found in the stomach. The hyper-CVAD/MA regimen may improve survival in these patients.展开更多
Objective:Mantle cell lymphoma(MCL)is a rare subtype of non-Hodgkin lymphoma(NHL)with high heterogeneity and a high recurrence rate.How heterogenous cell populations contribute to relapse remains to be elucidated.Meth...Objective:Mantle cell lymphoma(MCL)is a rare subtype of non-Hodgkin lymphoma(NHL)with high heterogeneity and a high recurrence rate.How heterogenous cell populations contribute to relapse remains to be elucidated.Methods:We performed single cell RNA sequencing(scRNA-seq)on approximately 4,000 bone marrow cells sampled from one patient with multidrug resistant MCL.We identified 10 subpopulations comprising 4 malignant B cell subtypes,3 T cell subtypes,2 dendritic cell subtypes and 1 natural killer(NK)cell subtype.Subsequently,we identified cell markers,including a series of genes associated with immune escape and drug resistance.In addition,we explored the roles of these genes in the mechanism of immune escape and drug resistance,and we verified the expression imbalance and clinical prognostic potential by using GEO datasets including 211 MCL samples.Results:The major immune escape mechanisms of MCL included anti-perforin activity,decreased immunogenicity and direct inhibition of apoptosis and cell killing,as mediated by type I and II B cells.The drug resistance mechanisms of different cell clusters included drug metabolism,DNA damage repair,apoptosis and survival promotion.Type III B cells closely communicate with other cells.The key genes involved in the resistance mechanisms showed dysregulated expression and may have significant clinical prognostic value.Conclusion:This study investigated potential immune escape and drug resistance mechanisms in MCL.The results may guide individualized treatment and promote the development of therapeutic drugs.展开更多
Objective: This study aims to explore the clinicopathologic features of 112 patients with mantle cell lymphoma (MCL). Methods: Data from 112 MCL cases were collected, and immunohistochemical assay was conducted. F...Objective: This study aims to explore the clinicopathologic features of 112 patients with mantle cell lymphoma (MCL). Methods: Data from 112 MCL cases were collected, and immunohistochemical assay was conducted. Fluorescence in situ hybridization (FISH) detected a break in the CCND 1 gene. The t-test was used in the statistical analysis. Results: All tumor cells in the 112 cases expressed B cell-related antigen, including 1 blastoid subtype and 1 polymorphic subtype. Among all cases, 106 expressed CD5 and 104 expressed cyclin D1. A break in the CCND1 gene was not found in 3 cases with CDS-MCL. IgH/CCND 1 polyploid was observed in 2 classic cases. Conclusion: MCL is a type of special immunophenotypic B-cell lymphoma, The prognoses ofblastoid and polymorphic subtypes are poor. Special subtypes should be classified during diagnosis.展开更多
Multiple lymphomatous polyposis(MLP)is an uncommon type of gastrointestinal lymphoma characterized by the presence of multiple polyps along the gastrointestinal tract.Most of this entity is in fact considered the coun...Multiple lymphomatous polyposis(MLP)is an uncommon type of gastrointestinal lymphoma characterized by the presence of multiple polyps along the gastrointestinal tract.Most of this entity is in fact considered the counterpart of gastrointestinal tract involvement for mantle cell lymphoma(MCL).To our knowledge,there have been no reports on[fluorine-18]-fluorodeoxy-glucose(18F-FDG)-positron emission tomography(PET)/computed tomography(CT)imaging for gastrointestinal MCL with MLP.We present the results of 18F-FDG PET/CT imaging in a patient with gastrointestinal tract involvement of MCL showing continuous MLP from the stomach to the rectum and intestinal intussusception.FDG-PET/CT findings were false negative in typical MLP spreading widely over the gastrointestinal tract,but uptake was noted in large lesions with deep infiltration considered atypical as MLP.On FDG-PET/CT imaging,the Ki-67proliferative index,which is a cell proliferation marker,showed neither correlation with the presence of uptake nor the maximum standardized uptake value.展开更多
Objective: To investigate the effects of CAL-101, particularly when combined with bortezomib(BTZ) on mantle cell lymphoma(MCL) cells, and to explore its relative mechanisms.Methods: MTT assay was applied to detect the...Objective: To investigate the effects of CAL-101, particularly when combined with bortezomib(BTZ) on mantle cell lymphoma(MCL) cells, and to explore its relative mechanisms.Methods: MTT assay was applied to detect the inhibitory effects of different concentrations of CAL-101. MCL cells were divided into four groups: control group, CAL-101 group, BTZ group, and CAL-101/BTZ group. The expression of PI3K-p110σ, AKT, ERK, p-AKT and p-ERK were detected by Western blot. The apoptosis rates of CAL-101 group, BTZ group, and combination group were detected by flow cytometry. The location changes of nuclear factor kappa-B(NF-κB) of 4 groups was investigated by NF-κB Kit exploring. Western blot was applied to detect the levels of caspase-3 and the phosphorylation of AKT in different groups. Results: CAL-101 dose- and time-dependently induced reduction in MCL cell viability. CAL-101 combined with BTZ enhanced the reduction in cell viability and apoptosis. Western blot analysis showed that CAL-101 significantly blocked the PI3K/AKT and ERK signaling pathway in MCL cells. The combination therapy contributed to the inactivation of NF-κB and AKT in MCL cell lines. However, cleaved caspase-3 was up-regulated after combined treatment. Conclusion: Our study showed that PI3K/p110σ is a novel therapeutic target in MCL, and the underlying mechanism could be the blocking of the PI3K/AKT and ERK signaling pathways. These findings provided a basis for clinical evaluation of CAL-101 and a rationale for its application in combination therapy, particularly with BTZ.展开更多
Objective:The function of euchromatic histone-lysine N-methyltransferase 2(EHMT2)has been studied in several cancers;however,little is known about its role in mantle cell lymphoma(MCL).Thus,this study aimed to charact...Objective:The function of euchromatic histone-lysine N-methyltransferase 2(EHMT2)has been studied in several cancers;however,little is known about its role in mantle cell lymphoma(MCL).Thus,this study aimed to characterize the significance and function of EHMT2 in MCL.Methods:EHMT2 expression in MCL and reactive hyperplasia(RH)were investigated by immunohistochemistry.Genome-wide analysis of DNA methylation was performed on EHMT2+MCL samples.The function of EHMT2 was determined by CCK&flow cytometry,and western blot assays.Gene expression profile analysis was performed before and after EHMT2 knockdown to search for EHMT2-regulated genes.Co-immunoprecipitation(Co-IP)experiments were conducted to identify the proteins interacting with EHMT2.Results:EHMT2 was expressed in 68.57%(24/35)of MCLs but not in any RHs.Genome-wide analysis of DNA methylation on EHMT2+MCLs revealed that multiple members of the HOX,FOX,PAX,SOX,and CDX families were hypermethylated or hypomethylated in EHMT2+MCLs.BIX0I294,a EHMT2 inhibitor,inhibited MCL cell growth and stalled cells in the G1 phase.Additionally,BIX01294 downregulated the expressions of cell cycle proteins,cyclin DI,CDK4,and P21,but upregulated the expressions of apoptosis-related proteins,Bax and caspase-3.Co-IP experiments revealed that EHMT2 interacted with UHRF1,HDAC1,and HDAC2 but not with HDCA3.After EHMT2 knockdown,multiple genes were regulated,including CD5 and CCND1,mostly enriched in the Tec kinase signaling pathway.In addition,several genes(e.g.,MARCH 1,CCDC50,HIP1,and WNT3)were aberrantly methylated in EHMT2+MCLs.Conclusions:For the first time,we determined the significance of EHMT2 in MCL and identified potential EHMT2-regulated genes.展开更多
BACKGROUND Mantle cell lymphoma(MCL)is a subtype of Non-Hodgkin’s lymphoma(NHL).MCL frequently affects extranodal sites while endobronchial involvement is uncommon.Only 5 cases of MCL with endobronchial involvement h...BACKGROUND Mantle cell lymphoma(MCL)is a subtype of Non-Hodgkin’s lymphoma(NHL).MCL frequently affects extranodal sites while endobronchial involvement is uncommon.Only 5 cases of MCL with endobronchial involvement have been previously reported.CASE SUMMARY A 56-year-old male patient arrived at the hospital complaining of a dry cough.A mass in the right upper lobe of the lung was revealed in Chest computed tomography(CT).Right lung hilar and mediastinal lymphadenopathies were also found by CT scan.The patient was diagnosed with central-type lung cancer with multiple lymph node metastases after positron emission tomography(PET)CT scan examination.The fiber optic bronchoscope examination revealed diffuse neoplasm infiltration in the inlet of the right up lobar bronchus.The patient was finally diagnosed with MCL based on the bronchoscopy and mediastinoscopy biopsy results.CONCLUSION MCL could masquerade as central type lung cancer.An endobronchial biopsy examination is necessary for the early diagnosis of MCL.展开更多
Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma. The disease has no known cure, which prompts the urgent need for novel therapeutic agents. Chromosomal region maintenance 1 (CRM...Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma. The disease has no known cure, which prompts the urgent need for novel therapeutic agents. Chromosomal region maintenance 1 (CRM1) may play a role in human neoplasia and serve as a novel target of cancer treatment. This study summarizes MCL pathogenesis and determines the involvement of CRM1 in the regulation of several vital signaling pathways contributing to MCL pathogenesis, including the pathways of cell cycle progression, DNA damage response, phosphoinositide kinase-3, nuclear factor-kB activation, and chromosomal stability. A preclinical study is also presented to compare the CRNI1 status in MCL cell lines and primary MCL cells with normal B cells, as well as the therapeutic efficiency of CRM1 inhibition in MCL in vitro and in vivo, which make these agents potential targets of novel MCL treatments.展开更多
Mantle cell lymphoma (MCL) is an aggressive nonHodgkin's lymphoma, originating from naive B-cells. The blastoid MCL tumors often show complex cytogenetic aberrations. In this review, we summarized the data availabl...Mantle cell lymphoma (MCL) is an aggressive nonHodgkin's lymphoma, originating from naive B-cells. The blastoid MCL tumors often show complex cytogenetic aberrations. In this review, we summarized the data available on immunoglobulin heavy-chain (IgH) genes rearrangement for their importance in suggesting the MCL normal counterpart B-cell. Some new data suggesting an antigen selection process were also presented in this review.展开更多
<strong>Objective:</strong> Therapeutic results of relapsed/refractory mantle cell lymphoma (R/R MCL) are very disappointing at present, and there is no standard effective treatment regimen. Ibrutinib has ...<strong>Objective:</strong> Therapeutic results of relapsed/refractory mantle cell lymphoma (R/R MCL) are very disappointing at present, and there is no standard effective treatment regimen. Ibrutinib has been proved to be effective for R/R MCL, however, the sample size of these individual clinical studies was relatively small. Hence, current clinical experience in its usage is still limited. It is necessary to systematically analyze the efficacy and adverse reactions of ibrutinib in the treatment of R/R MCL. <strong>Methods:</strong> The PubMed, Cochrane Library, and Embase databases were searched using English search terms, mantle cell lymphoma, MCL, and ibrutinib;the VIP, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were searched using the Chinese search terms, ibrutinib and mantle cell lymphoma. The extracted data were subjected to meta-analysis using R software to deduce the effective rate and occurrence rate of serious adverse reactions. <strong>Results:</strong> A total of 12 cohort studies were included in this analysis. The results demonstrated that ibrutinib could be an efficient therapy regimen for R/R MCL patients and the effect of combination therapy was better than that of single-drug therapy. During the treatment with ibrutinib, the adverse reactions mainly included hematological toxicity, infection, atrial fibrillation, and bleeding. <strong>Discussion:</strong> Our analysis showed ibrutinib is an optimal second-line treatment for R/R MCL, and the combination therapy is more effective than monotherapy as it was well-tolerated by the patients. Therefore, the combination of other drugs for R/R MCL should be considered for patients with poor efficacy of ibrutinib alone or relapse after treatment.展开更多
Objective:To study the effects of Wnt/β-catenin signaling pathway on the proliferation and invasive growth of cells in mantle cell lymphoma.Methods: Patients who were diagnosed with mantle cell lymphoma by lymph node...Objective:To study the effects of Wnt/β-catenin signaling pathway on the proliferation and invasive growth of cells in mantle cell lymphoma.Methods: Patients who were diagnosed with mantle cell lymphoma by lymph node biopsy in Tongji Hospital? Tongji Medical College Huazhong University of Science & Technology between March 2015 and May 2017 were selected as lymphoma group of the research, and patients who were diagnosed with reactive hyperplasia by lymph node biopsy during the same period were selected as the control group. The protein expression of Wnt/β-catenin signaling pathway molecules in lymph node tissues were determined by enzyme-linked immunosorbent assay kit, and the mRNA expression of proliferation genes and invasion genes were determined by fluorescence quantitative PCR kit.Results:β-catenin, p-GSK-3β and Tcf/Lef protein levels as well as C-myc, CyclinD1, Est-1, MMP9 and MMP26 mRNA expression in lymph node tissues of lymphoma group were significantly higher than those of control group whereas DKK1 and WIF-1 protein levels as well as Bax, Apaf1, Caspase-3, TNFAIP3, TIMP2 and TIMP4 mRNA expression were significantly lower than those of control group. C-myc, CyclinD1, Est-1, MMP9 and MMP26 mRNA expression in lymphoma tissues were positively correlated withβ-catenin, p-GSK-3β and Tcf/Lef protein levels, and negatively correlated with DKK1 and WIF-1 protein levels;Bax, Apaf1, Caspase-3, TNFAIP3, TIMP2 and TIMP4 mRNA expression were negatively correlated withβ-catenin, p-GSK-3β and Tcf/Lef protein levels, and positively correlated with DKK1 and WIF-1 protein levels.Conclusion: The activation of Wnt/β-catenin signaling pathway can promote the proliferation and invasive growth of cells in mantle cell lymphoma.展开更多
Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing ...Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1.We generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like phenotype.We showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell apoptosis.Treatment of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth.In this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.展开更多
Mantle cell lymphoma(MCL)is a B-cell malignancy with poor clinical outcome and undefined pathogenesis.Development of clinically relevant cellular models for MCL research is an urgent need.Our preliminary observations ...Mantle cell lymphoma(MCL)is a B-cell malignancy with poor clinical outcome and undefined pathogenesis.Development of clinically relevant cellular models for MCL research is an urgent need.Our preliminary observations lead the development of two novel hypotheses that we tested in this study:1.multicellular spheroid might be a unique growth mode of earlystage cells in MCL;2.MCL might be a polyclonal tumor.We made the following original observations that have not been reported:First,we have provided a new experiment method for enriching MCL early-stage cells and characterized the spheroid mode of growth as a unique feature of early-stage MCL cells in cell line as well as in clinical samples.Second,we have established a clinically relevant cellular model of MCL,the JeKo-1-spheroid cell line,that was highly enriched in early-stage sub-clones.JeKo-1-spheroid cells and the spheroid growing cells enriched from MCL patients exhibited comparably enhanced tumorigenic abilities and similar biological features.Third,Immunophenotypic analysis has revealed that MCL may be derived from precursor-B(pre-B),immature-B and mature-B cells,not only the mature-B cells as WHO classified in 2016.Fourth,MCL may be a polyclonal disease composed of CD19e/IgMe,CD19 e/IgMt,CD19t/IgMt three sub-clones,of which the CD19e/IgMt sub-clone might be the dominant sub-clone with the strongest tumorigenic ability.Fifth,CD19t/IgMe that differentiates MCL and normal B cells may represent a new marker for MCL early detection,minor residual disease monitoring after therapies and prognosis.展开更多
Background:Spontaneous regression has been reported in some indolent forms of lymphoma.Mantle cell lym-phoma(MCL)is an aggressive lymphoid neoplasm and has a poor prognosis.However,approximately 30%of MCL patients can...Background:Spontaneous regression has been reported in some indolent forms of lymphoma.Mantle cell lym-phoma(MCL)is an aggressive lymphoid neoplasm and has a poor prognosis.However,approximately 30%of MCL patients can exhibit indolent clinical behavior.To date,complete spontaneous regression of MCL has not been reported.Case presentation:We describe four cases of spontaneous regression of MCL.At the time of presentation,these patients were asymptomatic,with lymph node enlargement and mild to moderate fluorodeoxyglucose(FDG)uptake on FDG-positron emission tomography combined with computed tomography.One of the possible mechanisms of spontaneous regression of the tumor could be due to the host immune response through humoral and cellular immunity,which may have a role in the clearance of tumor cells.Conclusions:In this report,we support the use of a“wait and watch”strategy for MCL patients with no risk factors and indolent behavior.This strategy helps spare patients from further potentially harmful chemotherapy.In addition,we describe the phenomenon of spontaneous regression in MCL patients who are asymptomatic and have low-volume disease.展开更多
Mantle cell lymphoma(MCL)is a distinct histological type of B-cell lymphoma with a poor prognosis.Several agents,such as proteasome inhibitors,immunomodulatory drugs,and inhibitors of B cell lymphoma-2 and Bruton’s t...Mantle cell lymphoma(MCL)is a distinct histological type of B-cell lymphoma with a poor prognosis.Several agents,such as proteasome inhibitors,immunomodulatory drugs,and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory(r/r)MCL but often have short-term responses.Chimeric antigen receptor(CAR)T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma.However,long-term safety and tolerability associated with CAR T-cell therapy are not defined well,especially in MCL.In this report,we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy.CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient.This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL,who are generally elderly and have comorbid conditions.展开更多
Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from R...Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-I over-expressing and a control transfected cell line. Results: Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.展开更多
Mantle cell lymphoma is an aggressive subtype of B cell non-Hodgkin lymphoma. It can progress to leukemic phase but frank leukemic picture at initial presentation is not common. Leukemic phase indicates advance stage ...Mantle cell lymphoma is an aggressive subtype of B cell non-Hodgkin lymphoma. It can progress to leukemic phase but frank leukemic picture at initial presentation is not common. Leukemic phase indicates advance stage of the disease and generally associated with extensive extra-nodal involvement. Pericardial invasion has been reported, however we could not find a report of myocardial infiltration by this disease since the appraisal of the term "mantle cell lymphoma" in 1992. Here we report a case of cardiac involvement by mantle cell leukemia leading to cardiogenic shock which complicates the treatment decisions.展开更多
Chimeric antigen receptor(CAR)T-cell therapy has significantly improved outcomes for patients with relapsed/refractory large B-cell lymphoma,mantle cell lymphoma,and follicular lymphoma,with multiple FDA-approved CAR ...Chimeric antigen receptor(CAR)T-cell therapy has significantly improved outcomes for patients with relapsed/refractory large B-cell lymphoma,mantle cell lymphoma,and follicular lymphoma,with multiple FDA-approved CAR T products now commercially available.Ongoing studies seek to move CAR T-cells to earlier lines of therapy and to characterize the efficacy and safety of CAR T-cell approaches in additional lymphoma histologies including relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia.Other areas of active research address CAR T in combination with other lymphoma-directed therapies,and mechanisms of CAR T resistance.This review focuses on the FDA-approved anti-CD19 CAR T products for B-cell lymphomas,management of CAR T-cell-associated toxicities,approaches to bridging therapy,and ongoing clinical trials and future research directions across a broad range of lymphoma histologies.展开更多
基金supported by the Chongqing Natural Science Foundation(No.2023NSCQ-MSX3161 and No.cstc2020jcyj-msxmX1058)the National Natural Science Foundation of China(No.81800172).
文摘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.
文摘BACKGROUND Mantle cell lymphoma(MCL)of the gastrointestinal tract is a rare malignancy,accounting for about 0.2%of malignant colorectal tumors.MCL synchronous with rectal adenocarcinoma is extremely rare.We know of only a few cases reported in the literature.We describe the case of a patient with synchronous rectal adenocarcinoma and intestinal MCL.CASE SUMMARY A 63-year-old man was admitted to our hospital due to abdominal pain and hematochezia over the past month.The patient was diagnosed with middle rectal cancer cT2N0M0 and underwent surgery.However,we found a large tumor in the small intestine during surgery.The patient underwent total mesorectal excision for rectal cancer and resectioning of the ileal segment containing the large mass.Pathology and immunohistochemistry revealed the presence of both rectal adenocarcinoma and pathognomonic MCL stage IIE presenting as multiple lymphomatous polyposis.The patient subsequently underwent RDHAP/RCHOP chemotherapy and was maintained with rituximab.A Positron Emission Tomography and Computed Tomography(PET/CT)scan showed that the disease responded well to treatment without tumor-increased metabolism in the gastrointestinal tract.CONCLUSION Synchronous rectal adenocarcinoma and intestinal MCL presenting as multiple lymphomatous polyposis are extremely rare.MCL is often discovered fortuitously when rectal cancer is diagnosed.The coexistence of these tumors poses treatment challenges.
文摘AIM: To evaluate the endoscopic manifestations and prognoses of gastrointestinal (GI) mantle cell lymphoma (MCL). METHODS: A database search at the Department of Pathology of Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences revealed 57 MCL patients with GI involvement. Clinical records were available for 35 of the 57 patients from 21 institutions, and those 35 patients were enrolled in this study. We summarized the gross types of endoscopic features, event-free survival (EFS), and overall survival (OS) of those patients.RESULTS: Of the 35 patients, GI involvement in the esophagus, stomach, and duodenum was found in 2 (5.7%), 26 (74.3%), and 12 (34.3%) patients, respectively. Twenty-one of the 35 patients underwent colonoscopy; among them, GI involvement in the ileum, cecum, colon, and rectum was found in 10 (47.6%), 3 (14.3%), 12 (57.1%), and 10 (47.6%), respectively. Various lesions, such as superficial, protruded, fold thickening, or ulcerative, were found in the stomach, whereas multiple lymphomatous polyposis (MLP) was dominant from the duodenum to the rectum. Twelve patients were treated with a hyper-CVAD/MA regimen, and they had better OS (3-year rate, 88.3% vs 46.4%, P < 0.01) and better EFS (3-year rate, 66.7% vs 33.8%, P < 0.05) than the remaining 23 patients who were not treated with this regimen. CONCLUSION: MLP was a representative form of intestinal involvement, whereas a variety of lesions were found in the stomach. The hyper-CVAD/MA regimen may improve survival in these patients.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant No.81873450)the Open Research Fund from Beijing Advanced Innovation Center for Big Data-Based Precision Medicine,Beijing Tongren Hospital,Beihang University&Capital Medical University(Grant No.BHTR-KFJJ-202009)The authors thank Life-Ontology Biological Technology Co.,Ltd for assistance with bioinfbrmatics analysis.
文摘Objective:Mantle cell lymphoma(MCL)is a rare subtype of non-Hodgkin lymphoma(NHL)with high heterogeneity and a high recurrence rate.How heterogenous cell populations contribute to relapse remains to be elucidated.Methods:We performed single cell RNA sequencing(scRNA-seq)on approximately 4,000 bone marrow cells sampled from one patient with multidrug resistant MCL.We identified 10 subpopulations comprising 4 malignant B cell subtypes,3 T cell subtypes,2 dendritic cell subtypes and 1 natural killer(NK)cell subtype.Subsequently,we identified cell markers,including a series of genes associated with immune escape and drug resistance.In addition,we explored the roles of these genes in the mechanism of immune escape and drug resistance,and we verified the expression imbalance and clinical prognostic potential by using GEO datasets including 211 MCL samples.Results:The major immune escape mechanisms of MCL included anti-perforin activity,decreased immunogenicity and direct inhibition of apoptosis and cell killing,as mediated by type I and II B cells.The drug resistance mechanisms of different cell clusters included drug metabolism,DNA damage repair,apoptosis and survival promotion.Type III B cells closely communicate with other cells.The key genes involved in the resistance mechanisms showed dysregulated expression and may have significant clinical prognostic value.Conclusion:This study investigated potential immune escape and drug resistance mechanisms in MCL.The results may guide individualized treatment and promote the development of therapeutic drugs.
基金supported by grants from the National Clinical Key Specialty Construction Program,Provincial Natural Science Foundation of Fujian (Grant No.2012J01326)the Provincial Innovative Foundation of Fujian (Grant No.2012-cx-7)
文摘Objective: This study aims to explore the clinicopathologic features of 112 patients with mantle cell lymphoma (MCL). Methods: Data from 112 MCL cases were collected, and immunohistochemical assay was conducted. Fluorescence in situ hybridization (FISH) detected a break in the CCND 1 gene. The t-test was used in the statistical analysis. Results: All tumor cells in the 112 cases expressed B cell-related antigen, including 1 blastoid subtype and 1 polymorphic subtype. Among all cases, 106 expressed CD5 and 104 expressed cyclin D1. A break in the CCND1 gene was not found in 3 cases with CDS-MCL. IgH/CCND 1 polyploid was observed in 2 classic cases. Conclusion: MCL is a type of special immunophenotypic B-cell lymphoma, The prognoses ofblastoid and polymorphic subtypes are poor. Special subtypes should be classified during diagnosis.
基金Supported by Department of Cancer Pathology,Hokkaido University Graduate School of Medicine,Sapporo,Japan
文摘Multiple lymphomatous polyposis(MLP)is an uncommon type of gastrointestinal lymphoma characterized by the presence of multiple polyps along the gastrointestinal tract.Most of this entity is in fact considered the counterpart of gastrointestinal tract involvement for mantle cell lymphoma(MCL).To our knowledge,there have been no reports on[fluorine-18]-fluorodeoxy-glucose(18F-FDG)-positron emission tomography(PET)/computed tomography(CT)imaging for gastrointestinal MCL with MLP.We present the results of 18F-FDG PET/CT imaging in a patient with gastrointestinal tract involvement of MCL showing continuous MLP from the stomach to the rectum and intestinal intussusception.FDG-PET/CT findings were false negative in typical MLP spreading widely over the gastrointestinal tract,but uptake was noted in large lesions with deep infiltration considered atypical as MLP.On FDG-PET/CT imaging,the Ki-67proliferative index,which is a cell proliferation marker,showed neither correlation with the presence of uptake nor the maximum standardized uptake value.
基金supported by the National Natural Science Foundation of China (Grant No. 30672208, 81270603, and 31301161)Tianjin Natural Science Foundation of China (Grant No. 13JCYBJC22800)
文摘Objective: To investigate the effects of CAL-101, particularly when combined with bortezomib(BTZ) on mantle cell lymphoma(MCL) cells, and to explore its relative mechanisms.Methods: MTT assay was applied to detect the inhibitory effects of different concentrations of CAL-101. MCL cells were divided into four groups: control group, CAL-101 group, BTZ group, and CAL-101/BTZ group. The expression of PI3K-p110σ, AKT, ERK, p-AKT and p-ERK were detected by Western blot. The apoptosis rates of CAL-101 group, BTZ group, and combination group were detected by flow cytometry. The location changes of nuclear factor kappa-B(NF-κB) of 4 groups was investigated by NF-κB Kit exploring. Western blot was applied to detect the levels of caspase-3 and the phosphorylation of AKT in different groups. Results: CAL-101 dose- and time-dependently induced reduction in MCL cell viability. CAL-101 combined with BTZ enhanced the reduction in cell viability and apoptosis. Western blot analysis showed that CAL-101 significantly blocked the PI3K/AKT and ERK signaling pathway in MCL cells. The combination therapy contributed to the inactivation of NF-κB and AKT in MCL cell lines. However, cleaved caspase-3 was up-regulated after combined treatment. Conclusion: Our study showed that PI3K/p110σ is a novel therapeutic target in MCL, and the underlying mechanism could be the blocking of the PI3K/AKT and ERK signaling pathways. These findings provided a basis for clinical evaluation of CAL-101 and a rationale for its application in combination therapy, particularly with BTZ.
基金This study was supported by the National Natural Science Foundation of China(Grant No.81272277)the Natural Science Foundation of Shandong Province(Grant No.ZR2018MH020).
文摘Objective:The function of euchromatic histone-lysine N-methyltransferase 2(EHMT2)has been studied in several cancers;however,little is known about its role in mantle cell lymphoma(MCL).Thus,this study aimed to characterize the significance and function of EHMT2 in MCL.Methods:EHMT2 expression in MCL and reactive hyperplasia(RH)were investigated by immunohistochemistry.Genome-wide analysis of DNA methylation was performed on EHMT2+MCL samples.The function of EHMT2 was determined by CCK&flow cytometry,and western blot assays.Gene expression profile analysis was performed before and after EHMT2 knockdown to search for EHMT2-regulated genes.Co-immunoprecipitation(Co-IP)experiments were conducted to identify the proteins interacting with EHMT2.Results:EHMT2 was expressed in 68.57%(24/35)of MCLs but not in any RHs.Genome-wide analysis of DNA methylation on EHMT2+MCLs revealed that multiple members of the HOX,FOX,PAX,SOX,and CDX families were hypermethylated or hypomethylated in EHMT2+MCLs.BIX0I294,a EHMT2 inhibitor,inhibited MCL cell growth and stalled cells in the G1 phase.Additionally,BIX01294 downregulated the expressions of cell cycle proteins,cyclin DI,CDK4,and P21,but upregulated the expressions of apoptosis-related proteins,Bax and caspase-3.Co-IP experiments revealed that EHMT2 interacted with UHRF1,HDAC1,and HDAC2 but not with HDCA3.After EHMT2 knockdown,multiple genes were regulated,including CD5 and CCND1,mostly enriched in the Tec kinase signaling pathway.In addition,several genes(e.g.,MARCH 1,CCDC50,HIP1,and WNT3)were aberrantly methylated in EHMT2+MCLs.Conclusions:For the first time,we determined the significance of EHMT2 in MCL and identified potential EHMT2-regulated genes.
文摘BACKGROUND Mantle cell lymphoma(MCL)is a subtype of Non-Hodgkin’s lymphoma(NHL).MCL frequently affects extranodal sites while endobronchial involvement is uncommon.Only 5 cases of MCL with endobronchial involvement have been previously reported.CASE SUMMARY A 56-year-old male patient arrived at the hospital complaining of a dry cough.A mass in the right upper lobe of the lung was revealed in Chest computed tomography(CT).Right lung hilar and mediastinal lymphadenopathies were also found by CT scan.The patient was diagnosed with central-type lung cancer with multiple lymph node metastases after positron emission tomography(PET)CT scan examination.The fiber optic bronchoscope examination revealed diffuse neoplasm infiltration in the inlet of the right up lobar bronchus.The patient was finally diagnosed with MCL based on the bronchoscopy and mediastinoscopy biopsy results.CONCLUSION MCL could masquerade as central type lung cancer.An endobronchial biopsy examination is necessary for the early diagnosis of MCL.
基金supported in part by grants from Fujian Provincial Department of Science & Technology(2009-CXB-57/ 2011J01252)Bureau of Science & Technology of Xiamen,China (3502Z20094012)
文摘Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma. The disease has no known cure, which prompts the urgent need for novel therapeutic agents. Chromosomal region maintenance 1 (CRM1) may play a role in human neoplasia and serve as a novel target of cancer treatment. This study summarizes MCL pathogenesis and determines the involvement of CRM1 in the regulation of several vital signaling pathways contributing to MCL pathogenesis, including the pathways of cell cycle progression, DNA damage response, phosphoinositide kinase-3, nuclear factor-kB activation, and chromosomal stability. A preclinical study is also presented to compare the CRNI1 status in MCL cell lines and primary MCL cells with normal B cells, as well as the therapeutic efficiency of CRM1 inhibition in MCL in vitro and in vivo, which make these agents potential targets of novel MCL treatments.
文摘Mantle cell lymphoma (MCL) is an aggressive nonHodgkin's lymphoma, originating from naive B-cells. The blastoid MCL tumors often show complex cytogenetic aberrations. In this review, we summarized the data available on immunoglobulin heavy-chain (IgH) genes rearrangement for their importance in suggesting the MCL normal counterpart B-cell. Some new data suggesting an antigen selection process were also presented in this review.
文摘<strong>Objective:</strong> Therapeutic results of relapsed/refractory mantle cell lymphoma (R/R MCL) are very disappointing at present, and there is no standard effective treatment regimen. Ibrutinib has been proved to be effective for R/R MCL, however, the sample size of these individual clinical studies was relatively small. Hence, current clinical experience in its usage is still limited. It is necessary to systematically analyze the efficacy and adverse reactions of ibrutinib in the treatment of R/R MCL. <strong>Methods:</strong> The PubMed, Cochrane Library, and Embase databases were searched using English search terms, mantle cell lymphoma, MCL, and ibrutinib;the VIP, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were searched using the Chinese search terms, ibrutinib and mantle cell lymphoma. The extracted data were subjected to meta-analysis using R software to deduce the effective rate and occurrence rate of serious adverse reactions. <strong>Results:</strong> A total of 12 cohort studies were included in this analysis. The results demonstrated that ibrutinib could be an efficient therapy regimen for R/R MCL patients and the effect of combination therapy was better than that of single-drug therapy. During the treatment with ibrutinib, the adverse reactions mainly included hematological toxicity, infection, atrial fibrillation, and bleeding. <strong>Discussion:</strong> Our analysis showed ibrutinib is an optimal second-line treatment for R/R MCL, and the combination therapy is more effective than monotherapy as it was well-tolerated by the patients. Therefore, the combination of other drugs for R/R MCL should be considered for patients with poor efficacy of ibrutinib alone or relapse after treatment.
基金National Program on Key Basic Rescarch Projcct of China(973 Program)(No:2005CB5225007)Key Clinical Rescarch Projcct of the Ministry of Hcalth(No.:2010-2012)National Scicnce and Tochnology Support Program during the"11th Five-Year Plan"No.:2006BAI05A07)
文摘Objective:To study the effects of Wnt/β-catenin signaling pathway on the proliferation and invasive growth of cells in mantle cell lymphoma.Methods: Patients who were diagnosed with mantle cell lymphoma by lymph node biopsy in Tongji Hospital? Tongji Medical College Huazhong University of Science & Technology between March 2015 and May 2017 were selected as lymphoma group of the research, and patients who were diagnosed with reactive hyperplasia by lymph node biopsy during the same period were selected as the control group. The protein expression of Wnt/β-catenin signaling pathway molecules in lymph node tissues were determined by enzyme-linked immunosorbent assay kit, and the mRNA expression of proliferation genes and invasion genes were determined by fluorescence quantitative PCR kit.Results:β-catenin, p-GSK-3β and Tcf/Lef protein levels as well as C-myc, CyclinD1, Est-1, MMP9 and MMP26 mRNA expression in lymph node tissues of lymphoma group were significantly higher than those of control group whereas DKK1 and WIF-1 protein levels as well as Bax, Apaf1, Caspase-3, TNFAIP3, TIMP2 and TIMP4 mRNA expression were significantly lower than those of control group. C-myc, CyclinD1, Est-1, MMP9 and MMP26 mRNA expression in lymphoma tissues were positively correlated withβ-catenin, p-GSK-3β and Tcf/Lef protein levels, and negatively correlated with DKK1 and WIF-1 protein levels;Bax, Apaf1, Caspase-3, TNFAIP3, TIMP2 and TIMP4 mRNA expression were negatively correlated withβ-catenin, p-GSK-3β and Tcf/Lef protein levels, and positively correlated with DKK1 and WIF-1 protein levels.Conclusion: The activation of Wnt/β-catenin signaling pathway can promote the proliferation and invasive growth of cells in mantle cell lymphoma.
基金supported by National Key Research and Development Program of China(2021YFB3800800)to Di Chen and Liping Tongsupported by the National Natural Science Foundation of China(NSFC)grants(82030067,82161160342 and 82250710174)to Di Chen+1 种基金grant(82302757)to Ke Lusupported by SIAT Innovation Program for Excellent Young Researchers.
文摘Cyclin D1 has been recognized as an oncogene due to its abnormal upregulation in different types of cancers.Here,we demonstrated that cyclin D1 is SUMOylated,and we identified Itch as a specific E3 ligase recognizing SUMOylated cyclin D1 and mediating SUMO-induced ubiquitination and proteasome degradation of cyclin D1.We generated cyclin D1 mutant mice with mutations in the SUMOylation site,phosphorylation site,or both sites of cyclin D1,and found that double mutant mice developed a Mantle cell lymphoma(MCL)-like phenotype.We showed that arsenic trioxide(ATO)enhances cyclin D1 SUMOylation-mediated degradation through inhibition of cyclin D1 deSUMOylation enzymes,leading to MCL cell apoptosis.Treatment of severe combined immunodeficiency(SCID)mice grafted with MCL cells with ATO resulted in a significant reduction in tumor growth.In this study,we provide novel insights into the mechanisms of MCL tumor development and cyclin D1 regulation and discover a new strategy for MCL treatment.
基金We thank all the patients,healthy donors and their families,as well as The Affiliated Hospital of Southwest Medical University and Mianyang central hospital participating in this trial.We are thankful to the members in the Laboratory of Translational Cancer Stem Cell Research who are not listed in the authors.This work was funded by the National Natural Science Fund(Grant No.81272405)the Funds for Luzhou Medical College Applied Basic Research Plan(Grant No.2015-YJ122)+3 种基金the Key Research Project from Health and Family Planning Commission of Sichuan Province(Grant No.18ZD014)the National Natural Science Fund(Grant No.81450030)the Key Research Project of Sichuan Education Department(Grant No.14ZA0141)the Luzhou Science and Technology Project(Grant No.2014-S-47).
文摘Mantle cell lymphoma(MCL)is a B-cell malignancy with poor clinical outcome and undefined pathogenesis.Development of clinically relevant cellular models for MCL research is an urgent need.Our preliminary observations lead the development of two novel hypotheses that we tested in this study:1.multicellular spheroid might be a unique growth mode of earlystage cells in MCL;2.MCL might be a polyclonal tumor.We made the following original observations that have not been reported:First,we have provided a new experiment method for enriching MCL early-stage cells and characterized the spheroid mode of growth as a unique feature of early-stage MCL cells in cell line as well as in clinical samples.Second,we have established a clinically relevant cellular model of MCL,the JeKo-1-spheroid cell line,that was highly enriched in early-stage sub-clones.JeKo-1-spheroid cells and the spheroid growing cells enriched from MCL patients exhibited comparably enhanced tumorigenic abilities and similar biological features.Third,Immunophenotypic analysis has revealed that MCL may be derived from precursor-B(pre-B),immature-B and mature-B cells,not only the mature-B cells as WHO classified in 2016.Fourth,MCL may be a polyclonal disease composed of CD19e/IgMe,CD19 e/IgMt,CD19t/IgMt three sub-clones,of which the CD19e/IgMt sub-clone might be the dominant sub-clone with the strongest tumorigenic ability.Fifth,CD19t/IgMe that differentiates MCL and normal B cells may represent a new marker for MCL early detection,minor residual disease monitoring after therapies and prognosis.
基金Supported by the generous philanthropic contributions to The University of Texas MD Anderson Moon Shots Program and Zhejiang Provincial Natural Science Foundation of China(LY13H080003)。
文摘Background:Spontaneous regression has been reported in some indolent forms of lymphoma.Mantle cell lym-phoma(MCL)is an aggressive lymphoid neoplasm and has a poor prognosis.However,approximately 30%of MCL patients can exhibit indolent clinical behavior.To date,complete spontaneous regression of MCL has not been reported.Case presentation:We describe four cases of spontaneous regression of MCL.At the time of presentation,these patients were asymptomatic,with lymph node enlargement and mild to moderate fluorodeoxyglucose(FDG)uptake on FDG-positron emission tomography combined with computed tomography.One of the possible mechanisms of spontaneous regression of the tumor could be due to the host immune response through humoral and cellular immunity,which may have a role in the clearance of tumor cells.Conclusions:In this report,we support the use of a“wait and watch”strategy for MCL patients with no risk factors and indolent behavior.This strategy helps spare patients from further potentially harmful chemotherapy.In addition,we describe the phenomenon of spontaneous regression in MCL patients who are asymptomatic and have low-volume disease.
基金This study was supported by grants from the Shanghai Municipal Hospital New Frontier Technology Joint Research Project(No.SHDC12015108)the National Natural Science Foundation of China(Nos.81830004,31301118,and 81272325)the Fundamental Research Funds for the Central Universities(No.22120170004).
文摘Mantle cell lymphoma(MCL)is a distinct histological type of B-cell lymphoma with a poor prognosis.Several agents,such as proteasome inhibitors,immunomodulatory drugs,and inhibitors of B cell lymphoma-2 and Bruton’s tyrosine kinase have shown efficacy for relapsed or refractory(r/r)MCL but often have short-term responses.Chimeric antigen receptor(CAR)T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma.However,long-term safety and tolerability associated with CAR T-cell therapy are not defined well,especially in MCL.In this report,we described a 70-year-old patient with r/r MCL with 48-month duration of follow-up who achieved long-term remission after CAR T-cell therapy.CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient.This report suggested that CAR T-cell therapy is a promising treatment modality for patients with MCL,who are generally elderly and have comorbid conditions.
文摘Objective: Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cells over-express a guanine exchange factor (GEF), Rasgrf-1. This GEF increases active Ras as it catalyzes the removal of GDP from Ras so that GTP can bind and activate Ras. This study aims to study the mechanism of action of Rasgrf-1 in B-cell malignancies. Methods: N-terminus truncated Rasgrf-1 variants have a higher GEF activity as compared to the full-length transcript therefore a MCL cell line with stable over-expression of truncated Rasgrf-1 was established. The B-cell receptor (BCR) and chemokine signaling pathways were compared in the Rasgrf-I over-expressing and a control transfected cell line. Results: Cells over-expressing truncated form of Rasgrf-1 have a higher proliferative rate as compared to control transfected cells. BCR was activated by lower concentrations of anti-IgM antibody in Rasgrf-1 over-expressing cells as compared to control cells indicating that these cells are more sensitive to BCR signaling. BCR signaling also phosphorylates Rasgrf-1 that further increases its GEF function and amplifies BCR signaling. This activation of Rasgrf-1 in over-expressing cells resulted in a higher expression of phospho-ERK, AKT, BTK and PKC-alpha as compared to control cells. Besides BCR, Rasgrf-1 over-expressing cells were also more sensitive to microenvironment stimuli as determined by resistance to apoptosis, chemotaxis and ERK pathway activation. Conclusions: This GEF protein sensitizes B-cells to BCR and chemokine mediated signaling and also upregulates a number of other signaling pathways which promotes growth and survival of these cells.
文摘Mantle cell lymphoma is an aggressive subtype of B cell non-Hodgkin lymphoma. It can progress to leukemic phase but frank leukemic picture at initial presentation is not common. Leukemic phase indicates advance stage of the disease and generally associated with extensive extra-nodal involvement. Pericardial invasion has been reported, however we could not find a report of myocardial infiltration by this disease since the appraisal of the term "mantle cell lymphoma" in 1992. Here we report a case of cardiac involvement by mantle cell leukemia leading to cardiogenic shock which complicates the treatment decisions.
文摘Chimeric antigen receptor(CAR)T-cell therapy has significantly improved outcomes for patients with relapsed/refractory large B-cell lymphoma,mantle cell lymphoma,and follicular lymphoma,with multiple FDA-approved CAR T products now commercially available.Ongoing studies seek to move CAR T-cells to earlier lines of therapy and to characterize the efficacy and safety of CAR T-cell approaches in additional lymphoma histologies including relapsed/refractory follicular lymphoma and chronic lymphocytic leukemia.Other areas of active research address CAR T in combination with other lymphoma-directed therapies,and mechanisms of CAR T resistance.This review focuses on the FDA-approved anti-CD19 CAR T products for B-cell lymphomas,management of CAR T-cell-associated toxicities,approaches to bridging therapy,and ongoing clinical trials and future research directions across a broad range of lymphoma histologies.