Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia （T-ALL） cells and potential molecular mechanisms. Methods The anti-proliferation effect of resve...Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia （T-ALL） cells and potential molecular mechanisms. Methods The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTI- test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK. Results Resveratrol inhibited the proliferation and dose and time-dependent manner. It also induced cyclin-dependent kinase （CDK） inhibitors p21 and induced apoptosis and autophagy in T-ALL cells in a cell cycle arrest at G0/G1 phase via up regulating p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins （Mcl-1 and Bcl-2） and increased the expression of proapoptotic proteins （Bax, Bim, and Bad）, and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-11/LC3-1 and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced. Conclusion Our findings have suggested that resveratrol induces cell cycle arrest, apoptosis, and autophagy in T-ALL cells through inhibiting Akt/mTOR/p7OS6K/4E-BP1 and activating p38-MAPK signaling pathways. Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol. Therefore, the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.展开更多
Leukemia relapse is still the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell acute lymphoblastic leukemia (B-ALL). Relapsed patients with BALL after ...Leukemia relapse is still the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell acute lymphoblastic leukemia (B-ALL). Relapsed patients with BALL after allo-HSCT have a very short median survival. Minimal residual disease (MRD) is predictive of forthcoming hematological relapse after hematopoietic stem cell transplantation (HSCT);furthermore, eliminating MRD effectively prevents relapse. Donor lymphoblastic infusion (DLI) is the main established approach to treat B-ALL with MRD after allo-HSCT. However, about one-third of patients with MRD are non-responsive to DLI and their prognosis worsens. Although donor-derived cluster of differentiation (CD)19-directed chimeric antigen receptor-modified (CAR) T cells (CART19s) can potentially cure leukemia, the efficiency and safety of infusions with these cells have not yet been investigated in patients with MRD after HSCT. Between September 2014 and February 2018, six patients each received one or more infusions of CART19s from HSCT donors. Five (83.33%) achieved MRD-negative remission, and one case was not responsive to the administration of CAR T cells. Three of the six patients are currently alive without leukemia. No patient developed acute graft-versus-host disease (aGVHD), and no patient died of cytokine release syndrome. Donor-derived CAR T cell infusions seem to be an effective and safe intervention for patients with MRD in B-ALL after allo-HSCT and for those who were not responsive to DLI.展开更多
Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with aberrant T-cell developmental arrest. Individuals with relapsed T-ALL have limited therapeutic alternatives and po...Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with aberrant T-cell developmental arrest. Individuals with relapsed T-ALL have limited therapeutic alternatives and poor prognosis. The mitochondrial function is critical for the T-cell viability. The voltage-dependent anion channel 2 (VDAC2) in the mitochondrial outer membrane, interacts with pro-apoptotic BCL-2 proteins and mediates the apoptosis of several cancer cell lines. Objective: The aim of the current study is to explore the role of VDAC2 in T-ALL cell survival and proliferation. Methods: Publicly available datasets of RNA-seq results were analyzed for expression of VDAC isoforms and T-ALL cell lines were treated with a VDAC2 small molecular inhibitor erastin. A VDAC2 RNA interference (siRNA) was delivered to T-ALL cell lines using a retroviral vector. Functional assays were performed to investigate the VDAC2 siRNA impacts on cell proliferation, apoptosis and survival of T-ALL cells. Results: Our analysis found a high expression of VDAC2 mRNA in various T-ALL cell lines. Public datasets of T-ALL RNA-seq also showed that VDAC2 is highly expressed in T-ALL (116.2 ± 36.7), compared to control groups. Only two T-ALL cell lines showed sensitivity to erastin (20 μM) after 48 hours of incubation, including Jurkat (IC<sub>50</sub> = 3.943 μM) and Molt4 (IC<sub>50</sub> = 3.286 μM), while another two T-ALL cells (CUTLL1 and RPMI 8402) had unstable IC<sub>50</sub>. However, five T-ALL cell lines (LOUCY, CCRF-CEM, P12-ICHI, HPB-ALL, and PEER cells) showed resistance to erastin. On the contrary, all T-ALL cell lines genetically inhibited with VDAC2 siRNA led to more than 80% decrease in VDAC2 mRNA levels, and a Conclusion: VDAC2 is highly expressed in T-ALL cells. The inhibition of VDAC2 significantly decreased cell viability, increased apoptosis, reduced cell proliferation and caused cell cycle sub-G1 arrest of T-ALL cells.展开更多
T cell acute lymphoblastic leukemia(T-ALL) is an aggressive leukemia.However the poor prognosis and low morbidity restrict further analysis of the disease.Therefore there is an increasing demand to develop animal mode...T cell acute lymphoblastic leukemia(T-ALL) is an aggressive leukemia.However the poor prognosis and low morbidity restrict further analysis of the disease.Therefore there is an increasing demand to develop animal models for identifying novel therapeutic approaches.In this study,we inoculated the anti-mouse CD122 monoclonal antibody conditioned NOD/SCID mice with the leukemia cells from 9 T-ALL patients and 1 cell line via the tail vein.Four of the 9 patients and the cell line were successfully engrafted.Flow cytometry detected high percentage of human CD45 + cells in recipient mice.Immunohistochemistry showed infiltration of human CD45 + cells in different organs.Serial transplantation was also achieved.In vivo drug treatment showed that dexamethasone could extend survival,which was consistent with clinical observation.These results demonstrated that we successfully established 5 xenotransplantation models of T-ALL in anti-mCD122 mAb conditioned NOD/SCID mice,which recapitulated the characteristics of original disease.展开更多
BACKGROUND The clinical presentation of acute lymphoblastic lymphoma is highly varied.While prognosis is good, recurrence of disease can occur. Gastrointestinal relapse, including intussusception, is well-described bu...BACKGROUND The clinical presentation of acute lymphoblastic lymphoma is highly varied.While prognosis is good, recurrence of disease can occur. Gastrointestinal relapse, including intussusception, is well-described but the absence of abdominal pain in this setting is rare.CASE SUMMARY We report a 13-year-old male with B-cell precursor acute lymphoblastic leukemia in remission presenting with anemia and weight loss. Examination was significant for absence of abdominal pain, but a stool sample was positive for occult blood. Pan-endoscopy was performed with colonoscopy revealing a mass filling the colonic lumen. Biopsy of the mass confirmed recurrence of recurrent Bcell lymphoma. Computed tomography scan revealed ileocolic intussusception resulting from the tumor. This case is unusual in that the patient had no abdominal pain despite the presence of intussusception.CONCLUSION While intestinal involvement with lymphoma has been well described in the literature, presentation as painless intussusception has not been reported. This case report highlights the wide spectrum of clinical manifestations of recurrent Bcell lymphoma involving the gastrointestinal tract, in particular the near absence of symptoms despite the finding of intussusception.展开更多
BACKGROUND Infiltration of the breast by leukemic cells is uncommon but may manifest as an oncological emergency requiring prompt management.Extramedullary relapse of T-cell acute lymphoblastic leukemia(T-ALL)within t...BACKGROUND Infiltration of the breast by leukemic cells is uncommon but may manifest as an oncological emergency requiring prompt management.Extramedullary relapse of T-cell acute lymphoblastic leukemia(T-ALL)within the breast is exceedingly rare and there is paucity of data in the literature regarding this entity.No consensus exists on management of isolated extramedullary breast relapses of T-ALL.Herein,we report a case of isolated extramedullary breast relapse of T-ALL treated with breathing adapted radiation therapy(BART)using the active breathing control(ABC)system.CASE SUMMARY The patient was a 33-year-old female with diagnosis of T-ALL.She received intensive systemic chemotherapy that resulted in complete remission of her disease,and then underwent allogeneic hematopoietic stem cell transplantation.After a 15 mo period without symptoms and signs of progression,the patient presented with palpable masses in both breasts.She complained from severe pain and swelling of the breasts.Imaging workup showed bilateral breast lesions,and diagnosis of breast infiltration by leukemic cells was confirmed after immunohistopathological evaluation.The patient suffering from severe pain,discomfort,and swelling of both breasts due to leukemic infiltration was referred to the Radiation Oncology Department for symptomatic palliation.Whole breast irradiation was delivered to both breasts of the patient with BART using the ABC system.The patient had complete resolution of her symptoms after treatment with BART.CONCLUSION BART with the ABC system resulted in complete resolution of the patient’s symptoms due to leukemic infiltration of both breasts with T-ALL.This contemporary treatment technique should be preferred for radiotherapeutic management of patients with leukemic infiltration of the breasts to achieve effective symptomatic palliation.展开更多
Background: B-cell Acute lymphoblastic leukemia (B-ALL) is a neoplasm of lymphoblasts which are of B-cell lineage typically composed of small to medium sized blast cells, moderately condensed to dispersed chromatin wi...Background: B-cell Acute lymphoblastic leukemia (B-ALL) is a neoplasm of lymphoblasts which are of B-cell lineage typically composed of small to medium sized blast cells, moderately condensed to dispersed chromatin with scanty cytoplasm and inconspicuous nucleoli, involving the bone marrow and/or blood. Methods and materials: This is a prospective cross-sectional study in which 50 blood and/or bone marrow samples of newly diagnosed patients (B-ALL) were tested for immunophenotyping. All samples were prepared for surface and cytoplasmic markers including kappa and lambda human antibody for 10 minutes in dark place and then run by the Flow Cytometer. Results: 64% of the study populations were males and 36% were females. Cases were classified according to immunophenotype and the age into different subtypes and showed the following frequencies: Pro B-ALL (8%), early pre B-ALL (56%), common B-ALL (16%), Pre-B-ALL (14%) and Mature B-ALL (only 6%). Surface immunoglobulin was positive in 10% and negative in 90% of all patients, showing 100% positivity in mature B-ALL and totally negative in other subtypes. While cytoplasmic immunoglobulin was positive in 16% and negative in 84% of all patients and was positive in 100% of Pre-B-ALL and in 50% of mature B-ALL. Surface kappa was more expressed in mature B-ALL than lambda giving a ratio of 2:1, while cytoplasmic kappa:lambda was 6:1 in Pre-B-ALL. Conclusion: Kappa and lambda have important role in B-ALL classification which necessitates their presence in immunophenotyping of B-ALL.展开更多
基金supported by grants from the Department of Science and Technology of Sichuan Province,China (No.2008JY0029-1 and No.07FG002-024)research funds from the Program for Changjiang Scholars and Innovative-Research Team in University (No.IRT0935)
文摘Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia （T-ALL） cells and potential molecular mechanisms. Methods The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTI- test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK. Results Resveratrol inhibited the proliferation and dose and time-dependent manner. It also induced cyclin-dependent kinase （CDK） inhibitors p21 and induced apoptosis and autophagy in T-ALL cells in a cell cycle arrest at G0/G1 phase via up regulating p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins （Mcl-1 and Bcl-2） and increased the expression of proapoptotic proteins （Bax, Bim, and Bad）, and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-11/LC3-1 and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced. Conclusion Our findings have suggested that resveratrol induces cell cycle arrest, apoptosis, and autophagy in T-ALL cells through inhibiting Akt/mTOR/p7OS6K/4E-BP1 and activating p38-MAPK signaling pathways. Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol. Therefore, the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.
文摘Leukemia relapse is still the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell acute lymphoblastic leukemia (B-ALL). Relapsed patients with BALL after allo-HSCT have a very short median survival. Minimal residual disease (MRD) is predictive of forthcoming hematological relapse after hematopoietic stem cell transplantation (HSCT);furthermore, eliminating MRD effectively prevents relapse. Donor lymphoblastic infusion (DLI) is the main established approach to treat B-ALL with MRD after allo-HSCT. However, about one-third of patients with MRD are non-responsive to DLI and their prognosis worsens. Although donor-derived cluster of differentiation (CD)19-directed chimeric antigen receptor-modified (CAR) T cells (CART19s) can potentially cure leukemia, the efficiency and safety of infusions with these cells have not yet been investigated in patients with MRD after HSCT. Between September 2014 and February 2018, six patients each received one or more infusions of CART19s from HSCT donors. Five (83.33%) achieved MRD-negative remission, and one case was not responsive to the administration of CAR T cells. Three of the six patients are currently alive without leukemia. No patient developed acute graft-versus-host disease (aGVHD), and no patient died of cytokine release syndrome. Donor-derived CAR T cell infusions seem to be an effective and safe intervention for patients with MRD in B-ALL after allo-HSCT and for those who were not responsive to DLI.
文摘Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with aberrant T-cell developmental arrest. Individuals with relapsed T-ALL have limited therapeutic alternatives and poor prognosis. The mitochondrial function is critical for the T-cell viability. The voltage-dependent anion channel 2 (VDAC2) in the mitochondrial outer membrane, interacts with pro-apoptotic BCL-2 proteins and mediates the apoptosis of several cancer cell lines. Objective: The aim of the current study is to explore the role of VDAC2 in T-ALL cell survival and proliferation. Methods: Publicly available datasets of RNA-seq results were analyzed for expression of VDAC isoforms and T-ALL cell lines were treated with a VDAC2 small molecular inhibitor erastin. A VDAC2 RNA interference (siRNA) was delivered to T-ALL cell lines using a retroviral vector. Functional assays were performed to investigate the VDAC2 siRNA impacts on cell proliferation, apoptosis and survival of T-ALL cells. Results: Our analysis found a high expression of VDAC2 mRNA in various T-ALL cell lines. Public datasets of T-ALL RNA-seq also showed that VDAC2 is highly expressed in T-ALL (116.2 ± 36.7), compared to control groups. Only two T-ALL cell lines showed sensitivity to erastin (20 μM) after 48 hours of incubation, including Jurkat (IC<sub>50</sub> = 3.943 μM) and Molt4 (IC<sub>50</sub> = 3.286 μM), while another two T-ALL cells (CUTLL1 and RPMI 8402) had unstable IC<sub>50</sub>. However, five T-ALL cell lines (LOUCY, CCRF-CEM, P12-ICHI, HPB-ALL, and PEER cells) showed resistance to erastin. On the contrary, all T-ALL cell lines genetically inhibited with VDAC2 siRNA led to more than 80% decrease in VDAC2 mRNA levels, and a Conclusion: VDAC2 is highly expressed in T-ALL cells. The inhibition of VDAC2 significantly decreased cell viability, increased apoptosis, reduced cell proliferation and caused cell cycle sub-G1 arrest of T-ALL cells.
基金supported in part by the National Natural Science Foundation of China (No. 81025011 and No.81090414)
文摘T cell acute lymphoblastic leukemia(T-ALL) is an aggressive leukemia.However the poor prognosis and low morbidity restrict further analysis of the disease.Therefore there is an increasing demand to develop animal models for identifying novel therapeutic approaches.In this study,we inoculated the anti-mouse CD122 monoclonal antibody conditioned NOD/SCID mice with the leukemia cells from 9 T-ALL patients and 1 cell line via the tail vein.Four of the 9 patients and the cell line were successfully engrafted.Flow cytometry detected high percentage of human CD45 + cells in recipient mice.Immunohistochemistry showed infiltration of human CD45 + cells in different organs.Serial transplantation was also achieved.In vivo drug treatment showed that dexamethasone could extend survival,which was consistent with clinical observation.These results demonstrated that we successfully established 5 xenotransplantation models of T-ALL in anti-mCD122 mAb conditioned NOD/SCID mice,which recapitulated the characteristics of original disease.
文摘BACKGROUND The clinical presentation of acute lymphoblastic lymphoma is highly varied.While prognosis is good, recurrence of disease can occur. Gastrointestinal relapse, including intussusception, is well-described but the absence of abdominal pain in this setting is rare.CASE SUMMARY We report a 13-year-old male with B-cell precursor acute lymphoblastic leukemia in remission presenting with anemia and weight loss. Examination was significant for absence of abdominal pain, but a stool sample was positive for occult blood. Pan-endoscopy was performed with colonoscopy revealing a mass filling the colonic lumen. Biopsy of the mass confirmed recurrence of recurrent Bcell lymphoma. Computed tomography scan revealed ileocolic intussusception resulting from the tumor. This case is unusual in that the patient had no abdominal pain despite the presence of intussusception.CONCLUSION While intestinal involvement with lymphoma has been well described in the literature, presentation as painless intussusception has not been reported. This case report highlights the wide spectrum of clinical manifestations of recurrent Bcell lymphoma involving the gastrointestinal tract, in particular the near absence of symptoms despite the finding of intussusception.
文摘BACKGROUND Infiltration of the breast by leukemic cells is uncommon but may manifest as an oncological emergency requiring prompt management.Extramedullary relapse of T-cell acute lymphoblastic leukemia(T-ALL)within the breast is exceedingly rare and there is paucity of data in the literature regarding this entity.No consensus exists on management of isolated extramedullary breast relapses of T-ALL.Herein,we report a case of isolated extramedullary breast relapse of T-ALL treated with breathing adapted radiation therapy(BART)using the active breathing control(ABC)system.CASE SUMMARY The patient was a 33-year-old female with diagnosis of T-ALL.She received intensive systemic chemotherapy that resulted in complete remission of her disease,and then underwent allogeneic hematopoietic stem cell transplantation.After a 15 mo period without symptoms and signs of progression,the patient presented with palpable masses in both breasts.She complained from severe pain and swelling of the breasts.Imaging workup showed bilateral breast lesions,and diagnosis of breast infiltration by leukemic cells was confirmed after immunohistopathological evaluation.The patient suffering from severe pain,discomfort,and swelling of both breasts due to leukemic infiltration was referred to the Radiation Oncology Department for symptomatic palliation.Whole breast irradiation was delivered to both breasts of the patient with BART using the ABC system.The patient had complete resolution of her symptoms after treatment with BART.CONCLUSION BART with the ABC system resulted in complete resolution of the patient’s symptoms due to leukemic infiltration of both breasts with T-ALL.This contemporary treatment technique should be preferred for radiotherapeutic management of patients with leukemic infiltration of the breasts to achieve effective symptomatic palliation.
文摘Background: B-cell Acute lymphoblastic leukemia (B-ALL) is a neoplasm of lymphoblasts which are of B-cell lineage typically composed of small to medium sized blast cells, moderately condensed to dispersed chromatin with scanty cytoplasm and inconspicuous nucleoli, involving the bone marrow and/or blood. Methods and materials: This is a prospective cross-sectional study in which 50 blood and/or bone marrow samples of newly diagnosed patients (B-ALL) were tested for immunophenotyping. All samples were prepared for surface and cytoplasmic markers including kappa and lambda human antibody for 10 minutes in dark place and then run by the Flow Cytometer. Results: 64% of the study populations were males and 36% were females. Cases were classified according to immunophenotype and the age into different subtypes and showed the following frequencies: Pro B-ALL (8%), early pre B-ALL (56%), common B-ALL (16%), Pre-B-ALL (14%) and Mature B-ALL (only 6%). Surface immunoglobulin was positive in 10% and negative in 90% of all patients, showing 100% positivity in mature B-ALL and totally negative in other subtypes. While cytoplasmic immunoglobulin was positive in 16% and negative in 84% of all patients and was positive in 100% of Pre-B-ALL and in 50% of mature B-ALL. Surface kappa was more expressed in mature B-ALL than lambda giving a ratio of 2:1, while cytoplasmic kappa:lambda was 6:1 in Pre-B-ALL. Conclusion: Kappa and lambda have important role in B-ALL classification which necessitates their presence in immunophenotyping of B-ALL.
