The B-cell lymphoma/leukemia 11A （BCL11A） gene is essential for normal lymphoid development and has been associated with hematological malignancies. In the current study, the relative expression level of BCL11A in m...The B-cell lymphoma/leukemia 11A （BCL11A） gene is essential for normal lymphoid development and has been associated with hematological malignancies. In the current study, the relative expression level of BCL11A in malignant hematological cell lines was evaluated through real-time quantitative reverse transcription polymerase chain reaction （qRT-PCR）. METHODS The relative expression level of BCLllA mRNA in malignant hematological cell lines was determined through qRT- PCR using SYBR Green I dye. Glyceraldehyde-3-phosphate dehydro- genase was used as the reference gene to confirm the relative expression level of BCL11A gene mRNA. RESULTS The relative expression level of BCL11A mRNA in cell lines from B-cell malignancies was significantly higher compared with that from acute rnyeloid leukemia （P 〈 0.05）. Different cell lines with malignant B-cells exhibited a wide range of BCL11A expressions ranging from 27.37 to 93.38. CONCLUSION The overexpression of BCL11A gene mRNA in malignant B-cells might play a role in B-cell lymphoma/leukemia.展开更多
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 diag...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.展开更多
Background: High levels of MCL-1 and BCL-2 proteins have been found in Chronic Lymphocytic Leukemia (CLL), and inversely correlated with response to treatment. BCL-2/Bax ratio is the main director of apoptosis in CLL....Background: High levels of MCL-1 and BCL-2 proteins have been found in Chronic Lymphocytic Leukemia (CLL), and inversely correlated with response to treatment. BCL-2/Bax ratio is the main director of apoptosis in CLL. The study aimed to clarify the prognostic role of MCL-1, BCL-2 and BCL-2/ Bax ratio in B-CLL. Patients & method: Estimation of MCL-1, BCL-2 and Bax expressions by a flow cytometry in 45 B-CLL patients and the prognostic value of these markers were correlated with other well-known established prognostic markers and treatment response. Results: MCL-1 was expressed in 60% of cases while BCL-2 was expressed in 82.2% of cases. MCL-1 expression was significantly high in male gender, short lymphocyte doubling time (LDT), and high expression of CD 38 (p β2M, CD38 expression), low ZAP-70 expression, splenomegaly and higher Rai stage were significantly increased in patients with high expression of BCL-2 (p β2M, high C-D38 expression, low ZAP-70 expression, the poor cytogenetic and splenomegaly in patients with high expression of BCL-2/ Bax ratio (p In conclusion: MCL-1, BCL-2 expressions and BCL-2/Bax ratio could be useful potential predictive and prognostic markers in B-CLL.展开更多
AIM： To assess the significance of chromosome translo- cation t（11;18）（q21;q21）, B-cell lymphoma 10 （BCL-10） protein and He/icobacter py/ori （H. py/on） infection in gastric mucosa-associated lymphoid tissue ...AIM： To assess the significance of chromosome translo- cation t（11;18）（q21;q21）, B-cell lymphoma 10 （BCL-10） protein and He/icobacter py/ori （H. py/on） infection in gastric mucosa-associated lymphoid tissue （MALT） lymphoma in Colombia.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
Background:Patients with relapsed/refractory B-cell lymphomas have limited treatment options.GERSHWIN is an open-label,single-arm,phase Ib study of obinutuzumab monotherapy in Chinese patients with histologically docu...Background:Patients with relapsed/refractory B-cell lymphomas have limited treatment options.GERSHWIN is an open-label,single-arm,phase Ib study of obinutuzumab monotherapy in Chinese patients with histologically docu-mented CD20+relapsed/refractory chronic lymphocytic leukemia(CLL),diffuse large B-cell lymphoma(DLBCL),or follicular lymphoma(FL).The primary outcome measure of pharmacokinetics has been previously reported.We now present data on the secondary endpoint measures(e.g.,safety,and efficacy and pharmacodynamics).Methods:Patients received 1000 mg obinutuzumab intravenously on days 1,8,and 15 of cycle 1(CLL patients;first dose split over 2 days),and on day 1 of cycles 2-8.Each cycle lasted for 21 days;the treatment period was 24 weeks.All subjects receiving at least one dose of obinutuzumab were included in the analysis of safety,efficacy,as well as pharmacodynamics.Results:A total of 48 patients(>18 years of age)were enrolled(CLL:12;DLBCL:23;FL:13).The subjects received a median of two lines of anticancer treatment prior to the enrollment.Thirty-five patients(72.9%)had at least one adverse event(AE).The most frequent AE was infusion-related reactions(15 patients;31.3%),followed by pyrexia(11 patients;22.9%).Treatment-related AEs were reported in 28 patients(58.3%),and included one death(interstitial lung disease).End-of-treatment(EoT)response rate was 33.3%.Best overall response rate was 47.9%.Most CLL patients achieved a partial response at EoT(58.3%).CD19+depletion occurred in 75.0%of the patients with CLL,and all patients with FL and DLBCL.Conclusions:The safety and efficacy of obinutuzumab monotherapy in Chinese patients with B-cell lymphomas were similar to that observed in previous studies in non-Chinese patients;no new safety signals were observed.展开更多
Importance Burkitt lymphoma with bone marrow involvement and Burkitt leukemia behave aggressively.Thus far,there are limited data concerning survival and toxicity in Chinese children with Burkitt lymphoma or Burkitt l...Importance Burkitt lymphoma with bone marrow involvement and Burkitt leukemia behave aggressively.Thus far,there are limited data concerning survival and toxicity in Chinese children with Burkitt lymphoma or Burkitt leukemia who have undergone treatment with the non-Hodgkin’s lymphoma Berlin-Frankfurt-Münster-90/95(NHL-BFM-90/95)protocol.Objective To analyze outcomes and toxicity in pediatric patients who exhibit Burkitt lymphoma with bone marrow involvement or Burkitt leukemia following treatment with the NHL-BFM-90/95 protocol.Methods Patients aged<18 years with bone marrow involvement/leukemia who were treated with the NHL-BFM-90/95 protocol,with or without rituximab,in Sun Yat-Sen University Cancer Center from April 2004 to December 2018 were included in this retrospective analysis.Results Twenty-five patients were eligible.Burkitt lymphoma with bone marrow involvement and Burkitt leukemia were present in 10 and 15 patients,respectively.Central nervous system infiltration was not observed in any patients.All patients underwent chemotherapy involving NHL-BFM-90/95 protocol.Six courses of treatment were administered to each patient(v-AA-BB-CC-AA-BB-CC).The BFM-90/95 plus rituximab protocol was administered to 13 patients.The median follow-up interval was 31.9 months(range,2.5–158 months).Of the 25 patients,four died:three died of tumor progression and one died of therapy abandonment after relief of tumor lysis syndrome.The estimated 5-year event-free survival and overall survival rates were both 85.8%±5.0%.Interpretation Chinese pediatric patients who exhibit Burkitt lymphoma with bone marrow involvement or Burkitt leukemia can achieve optimal treatment outcomes and exhibit good tolerance when using the NHL-BFM-90/95 protocol.展开更多
Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia,particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy.Two classes of agent...Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia,particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy.Two classes of agent in particular,the Bruton tyrosine kinase inhibitors(e.g.,ibrutinib)and the B-cell lymphoma 2 inhibitor,venetoclax,induce high response rates and durable remissions in the relapsed/refractory and frontline settings.However,maturing clinical data have revealed promises and pitfalls for both agents.These drugs induce remissions and disease control in the majority of patients,often in situations where modest efficacy would be expected with traditional chemoimmunotherapy approaches.Unfortunately,in the relapsed and refractory setting,both agents appear to be associated with an inevitable risk of disease relapse and progression.Emerging patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease progression.Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients’quality and length of life.Rational drug combinations,optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.展开更多
文摘The B-cell lymphoma/leukemia 11A （BCL11A） gene is essential for normal lymphoid development and has been associated with hematological malignancies. In the current study, the relative expression level of BCL11A in malignant hematological cell lines was evaluated through real-time quantitative reverse transcription polymerase chain reaction （qRT-PCR）. METHODS The relative expression level of BCLllA mRNA in malignant hematological cell lines was determined through qRT- PCR using SYBR Green I dye. Glyceraldehyde-3-phosphate dehydro- genase was used as the reference gene to confirm the relative expression level of BCL11A gene mRNA. RESULTS The relative expression level of BCL11A mRNA in cell lines from B-cell malignancies was significantly higher compared with that from acute rnyeloid leukemia （P 〈 0.05）. Different cell lines with malignant B-cells exhibited a wide range of BCL11A expressions ranging from 27.37 to 93.38. CONCLUSION The overexpression of BCL11A gene mRNA in malignant B-cells might play a role in B-cell lymphoma/leukemia.
基金Supported by the National Natural Science Foundation of China,No.81700130Nanjing Medical University Science and Technology Development Fund.
文摘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.
文摘Background: High levels of MCL-1 and BCL-2 proteins have been found in Chronic Lymphocytic Leukemia (CLL), and inversely correlated with response to treatment. BCL-2/Bax ratio is the main director of apoptosis in CLL. The study aimed to clarify the prognostic role of MCL-1, BCL-2 and BCL-2/ Bax ratio in B-CLL. Patients & method: Estimation of MCL-1, BCL-2 and Bax expressions by a flow cytometry in 45 B-CLL patients and the prognostic value of these markers were correlated with other well-known established prognostic markers and treatment response. Results: MCL-1 was expressed in 60% of cases while BCL-2 was expressed in 82.2% of cases. MCL-1 expression was significantly high in male gender, short lymphocyte doubling time (LDT), and high expression of CD 38 (p β2M, CD38 expression), low ZAP-70 expression, splenomegaly and higher Rai stage were significantly increased in patients with high expression of BCL-2 (p β2M, high C-D38 expression, low ZAP-70 expression, the poor cytogenetic and splenomegaly in patients with high expression of BCL-2/ Bax ratio (p In conclusion: MCL-1, BCL-2 expressions and BCL-2/Bax ratio could be useful potential predictive and prognostic markers in B-CLL.
基金Supported by A grant from Universidad Nacional de Colombia
文摘AIM： To assess the significance of chromosome translo- cation t（11;18）（q21;q21）, B-cell lymphoma 10 （BCL-10） protein and He/icobacter py/ori （H. py/on） infection in gastric mucosa-associated lymphoid tissue （MALT） lymphoma in Colombia.
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.
基金GERSHWIN was sponsored by F.Hoffmann-La Roche Ltd.Medical Writing supportunder the direction of the lead author,was provided by Elizabeth Johnson of Gardiner-Caldwell Communications,and was funded by F.Hoffmann-La Roche Ltd.
文摘Background:Patients with relapsed/refractory B-cell lymphomas have limited treatment options.GERSHWIN is an open-label,single-arm,phase Ib study of obinutuzumab monotherapy in Chinese patients with histologically docu-mented CD20+relapsed/refractory chronic lymphocytic leukemia(CLL),diffuse large B-cell lymphoma(DLBCL),or follicular lymphoma(FL).The primary outcome measure of pharmacokinetics has been previously reported.We now present data on the secondary endpoint measures(e.g.,safety,and efficacy and pharmacodynamics).Methods:Patients received 1000 mg obinutuzumab intravenously on days 1,8,and 15 of cycle 1(CLL patients;first dose split over 2 days),and on day 1 of cycles 2-8.Each cycle lasted for 21 days;the treatment period was 24 weeks.All subjects receiving at least one dose of obinutuzumab were included in the analysis of safety,efficacy,as well as pharmacodynamics.Results:A total of 48 patients(>18 years of age)were enrolled(CLL:12;DLBCL:23;FL:13).The subjects received a median of two lines of anticancer treatment prior to the enrollment.Thirty-five patients(72.9%)had at least one adverse event(AE).The most frequent AE was infusion-related reactions(15 patients;31.3%),followed by pyrexia(11 patients;22.9%).Treatment-related AEs were reported in 28 patients(58.3%),and included one death(interstitial lung disease).End-of-treatment(EoT)response rate was 33.3%.Best overall response rate was 47.9%.Most CLL patients achieved a partial response at EoT(58.3%).CD19+depletion occurred in 75.0%of the patients with CLL,and all patients with FL and DLBCL.Conclusions:The safety and efficacy of obinutuzumab monotherapy in Chinese patients with B-cell lymphomas were similar to that observed in previous studies in non-Chinese patients;no new safety signals were observed.
基金The authors would like to thank the participants and study staff of Sun Yat-sen Univesity Cancer Center for their contributions to this article.
文摘Importance Burkitt lymphoma with bone marrow involvement and Burkitt leukemia behave aggressively.Thus far,there are limited data concerning survival and toxicity in Chinese children with Burkitt lymphoma or Burkitt leukemia who have undergone treatment with the non-Hodgkin’s lymphoma Berlin-Frankfurt-Münster-90/95(NHL-BFM-90/95)protocol.Objective To analyze outcomes and toxicity in pediatric patients who exhibit Burkitt lymphoma with bone marrow involvement or Burkitt leukemia following treatment with the NHL-BFM-90/95 protocol.Methods Patients aged<18 years with bone marrow involvement/leukemia who were treated with the NHL-BFM-90/95 protocol,with or without rituximab,in Sun Yat-Sen University Cancer Center from April 2004 to December 2018 were included in this retrospective analysis.Results Twenty-five patients were eligible.Burkitt lymphoma with bone marrow involvement and Burkitt leukemia were present in 10 and 15 patients,respectively.Central nervous system infiltration was not observed in any patients.All patients underwent chemotherapy involving NHL-BFM-90/95 protocol.Six courses of treatment were administered to each patient(v-AA-BB-CC-AA-BB-CC).The BFM-90/95 plus rituximab protocol was administered to 13 patients.The median follow-up interval was 31.9 months(range,2.5–158 months).Of the 25 patients,four died:three died of tumor progression and one died of therapy abandonment after relief of tumor lysis syndrome.The estimated 5-year event-free survival and overall survival rates were both 85.8%±5.0%.Interpretation Chinese pediatric patients who exhibit Burkitt lymphoma with bone marrow involvement or Burkitt leukemia can achieve optimal treatment outcomes and exhibit good tolerance when using the NHL-BFM-90/95 protocol.
文摘Targeted agents have significantly improved outcomes for patients with chronic lymphocytic leukemia,particularly high-risk subgroups for whom chemoimmunotherapy previously offered limited efficacy.Two classes of agent in particular,the Bruton tyrosine kinase inhibitors(e.g.,ibrutinib)and the B-cell lymphoma 2 inhibitor,venetoclax,induce high response rates and durable remissions in the relapsed/refractory and frontline settings.However,maturing clinical data have revealed promises and pitfalls for both agents.These drugs induce remissions and disease control in the majority of patients,often in situations where modest efficacy would be expected with traditional chemoimmunotherapy approaches.Unfortunately,in the relapsed and refractory setting,both agents appear to be associated with an inevitable risk of disease relapse and progression.Emerging patterns of resistance are being described for both agents but a common theme appears to be multiple sub-clonal drivers of disease progression.Understanding these mechanisms and developing effective and safe methods to circumvent the emergence of resistance will determine the longer-term utility of these agents to improve patients’quality and length of life.Rational drug combinations,optimised scheduling and sequencing of therapy will likely hold the key to achieving these important goals.
