Objective： The aim of the study was to investigate the expression pattern of hematopoietic transcription factor GATA-1, -2 and -3 genes in leukemic bone marrow （BM） micreenvironment [including bone marrow stremal c...Objective： The aim of the study was to investigate the expression pattern of hematopoietic transcription factor GATA-1, -2 and -3 genes in leukemic bone marrow （BM） micreenvironment [including bone marrow stremal cells （BMSCs） and BM hematopoietic cells]. Methods： Mononuclear cells were isolated from BM of patients with acute myeloid leukemia （AML）, chronic myelogenous leukemia （CML）, or acute lymphoblasUc leukemia （ALL）. Adherent cells （BMSCs） and nonadherent ceils （BM hematopoietic cells） were collected after long-term culture in vitro. The semi-quantitative expression levels of GATA genes in the BMSCs or BM hematopoietic cells from patients with leukemia were analyzed by using RT-PCR-ELISA and com- pared with normal controls. Results： The expression level of GATA-1 gene in the BMSCs from CML group was significantly lower than that of the normal controls. The expression level of GATA-3 gene in the BMSCs from ALL was higher than that of the normal controls, but that from CML was lower than the normal controls. Dominant expression of GATA-3 gene was found in the normal BM hematopoietic cells. The dominant expression of GATA-2 gene was found in the normal BMSCs and the BMSCs from CML, whereas the dominant expression of GATA-3 gene was detected in the BMSCs from AML. Conclusion： GATA-1, -2 and -3 genes might play a role in hematopoiesis regulation in leukemia, and the changes of expression pattern of GATA genes might influence the hematopoiesis in BM microenvironment and relate to the pathogenesis and development of leukemia.展开更多
In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment,acute myeloid leukemia(AML)cells continuously adjust their metabolic state.To meet the biochemical demands of their ...In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment,acute myeloid leukemia(AML)cells continuously adjust their metabolic state.To meet the biochemical demands of their increased proliferation,AML cells strongly depend on mitochondrial oxidative phosphorylation(OXPHOS).Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation(FAO),which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance.For targeting these metabolic vulnerabilities of AML cells,inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential.Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells,enabling them to acquire resistance against OXPHOS and FAO inhibitors.These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors.Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.展开更多
Multiple myeloma(MM)is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow(BM).The interaction between MM cells and the BM microenvironment,a...Multiple myeloma(MM)is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow(BM).The interaction between MM cells and the BM microenvironment,and specifically BM mesenchymal stem cells(BM-MSCs),has a key role in the pathophysiology of this disease.Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs,aiding the progression of this hematological tumor.The relation of MM cells with the resident BM-MSCs is a two-way interaction.MM modulate the behavior of BM-MSCs altering their expression profile,proliferation rate,osteogenic potential,and expression of senescence markers.In turn,modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression.The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs,long non-coding RNAs or other molecules.However,the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes.Thus,understanding the way this communication works and developing strategies to interfere in the process,would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.展开更多
Bone marrow(BM)microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis.In analogy to normal hematopoiesis,leukemogenesis is originated from leukemic stem cells...Bone marrow(BM)microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis.In analogy to normal hematopoiesis,leukemogenesis is originated from leukemic stem cells(LSCs)which gives rise to more differentiated malignant cells.Leukemia cells occupy BM niches and reconstruct them to support leukemogenesis.The abnormal BM niches are the main sanctuary of LSCs where they can evade chemotherapy-induced death and acquire drug resistance.In this review,we focus on the protective effects of BM niche cells on acute lymphoblastic leukemia cells.展开更多
Objective:To evaluate the effect of ligust razine on bone marrow hematopoietic microenvironment and signal transduction in irradiation injured mice.Methods:After being irradiated by 6.0 Gy 60 Co γ -ray, the mi...Objective:To evaluate the effect of ligust razine on bone marrow hematopoietic microenvironment and signal transduction in irradiation injured mice.Methods:After being irradiated by 6.0 Gy 60 Co γ -ray, the mice in the ligustrazine group were orally given ligustrazine 4 mg/mouse twice a day to the end of the experiment. For the control group, normal saline was given instead of ligustrazine and the mice in the normal group was untreated. The mice were sacrificed separately on the 3rd, 7th and 14th day after radiation, bone marrow of them was taken and m anaged as follows:(1) Make stromal cell culture to observe the growth state and the expression of focal adhesion kinase (FAK) of the cells; (2) Make the bo ne marrow section to examine the pathological and immunohistochemistry changes, including the expression of fetal liver kinase-1 (Flk-1) and F VIII :RAg. The data were recorded and compared among groups.Results:After radiation, the hematopoietic cells in bo ne marrow decreased and the micro vessels dilated and congested with bleeding; bone mar row became thinner, red colored with cells of irregular shape and few cells adhere to the bottom of culture flask. These changes began to recover at the 7th day and approached to normal within 2 weeks. The recovery was better, earlier and quick er in the ligustrazine group than that in the control group. The expression lev els of Flk-1 decreased significantly.Conclusion: Ligustrazine could promote the recovery of hematopoietic function of radiation damaged bone marrow, the mechanisms might be through imp roving the microenvironment and signal transduction path for recovery.展开更多
Acute lymphoblastic leukemia(ALL)is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations.With the introduction ...Acute lymphoblastic leukemia(ALL)is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations.With the introduction of intensive multi-agent chemotherapeutic regimens,survival rates for ALL have improved dramatically over the past several decades,though survival rates for adult ALL continue to lag behind those of pediatric ALL.Resistance to chemotherapy remains a significant obstacle in the treatment of ALL,and chemoresistance due to molecular alterations within ALL cells have been described.In addition to these cell-intrinsic factors,the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance,and it is now known that stromal cells within the bone marrow microenvironment,through direct cell-cell interactions and through the release of lymphoid-acting soluble factors,contribute to ALL pathogenesis and chemoresistance.This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context.展开更多
To study the expression of the bFGF and its receptor in the mouse bone marrow by treatment with acute radioactive injury and Ligustrazine, 56 mice were divided into 3 groups: normal group, radiation injured group and...To study the expression of the bFGF and its receptor in the mouse bone marrow by treatment with acute radioactive injury and Ligustrazine, 56 mice were divided into 3 groups: normal group, radiation injured group and Ligustrazine group. After irradiation by 6.0 Gy 60 Co γ ray, each mouse was orally given 0.1 ml Ligustrazine twice a day for 13 days in Ligustrazine group, and each mouse in radiation injured group was orally given equal amount of saline. On the 3rd, 7th, 14th day after irradiation, bone marrow mono nuclear cells (BMMNC) were counted, and the expression levels of bFGF and bFGFR in bone marrow were evaluated by immunohistochemistry and flow cytometry analysis respectively. On the 3rd, 7th, 14th day after irradiation, expression of bFGF in bone marrow were significantly lower than in normal group ( P <0.05 or P <0.01). Expressions of bFGF and bFGFR were much higher in Ligustrazine treated group than that in the control group ( P <0.05 or P <0.01). Ligustrazine potentiate the expression of bFGF and bFGFR in bone marrow MNC to recover the bone marrow hematopoiesis inductive microenvironment, which is one of the mechanisms by which Ligustrazine rebuild the bone marrow hematopoiesis after acute radioactive injury.展开更多
Objective: To explore the effect of gamma irradiation on nuclear factor-kappa B in cultured bone marrow stromal cells. Methods: Immunocytochemistry, Western blot and electrophoretic mobility shift assay (EMSA) were us...Objective: To explore the effect of gamma irradiation on nuclear factor-kappa B in cultured bone marrow stromal cells. Methods: Immunocytochemistry, Western blot and electrophoretic mobility shift assay (EMSA) were used. Results: The expression of NF-kB in cultured mouse bone marrow stromal cells (BM-SCs) on the level of protein was elevated after exposure to 60Co in the dosage of 8. 0 Gy with the use of im-munocytochemistry and Western blot. The activity of nuclear factor-kappa B in cultured BMSCs was significantly increased after exposure to gamma irradiation by using EMSA. The activity peak was at the 4th h after irradiation. Conclusion: Our results suggest that the activation of nuclear factor-kappa B in the BMSCs after irradiation may be involved in the protection of BMSCs against apoptosis and in the recovery of hematopoiesis after radiation.展开更多
Background: Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects mi...Background: Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. Methods: Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca^(2+)-related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. Results: Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca ^(2+ )is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. Conclusions: Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.展开更多
Leukemia stem cells in acute myeloid leukemia(AML)can persist within unique bone marrow niches similar to those of healthy hematopoietic stem cells and resist chemotherapy.In the context of AML,endothelial cells(ECs)a...Leukemia stem cells in acute myeloid leukemia(AML)can persist within unique bone marrow niches similar to those of healthy hematopoietic stem cells and resist chemotherapy.In the context of AML,endothelial cells(ECs)are crucial components of these niches that appear to promote malignant expansion despite treatment.To better understand these interactions,we developed a real-time cell cycle-tracking mouse model of AML(Fucci-MA9)with an aim of unraveling why quiescent leukemia cells are more resistant to chemotherapy than cycling cells and proliferate during disease relapse.We found that quiescent leukemia cells were more prone to escape chemotherapy than cycling cells,leading to relapse and proliferation.Importantly,post-chemotherapy resting leukemia cells tended to localize closer to blood vessels.Mechanistically,after chemotherapy,resting leukemia cells interacted with ECs,promoting their adhesion and anti-apoptotic capacity.Further,expression analysis of ECs and leukemia cells during AML,after chemotherapy,and after relapse revealed the potential of suppressing the post-chemotherapy inflammatory response to regulate the functions of leukemia cells and ECs.These findings highlight the role of leukemia cells in evading chemotherapy by seeking refuge near blood vessels and provide important insights and directions for future AML research and treatment.展开更多
To observe the leucocyte increasing effect of Shuanghuang Shengbai Granule (SHSBG) in tumor patients treated by chemotherapy and the bone marrow microenvironment protecting effect in mice.Methods: Patients of non-smal...To observe the leucocyte increasing effect of Shuanghuang Shengbai Granule (SHSBG) in tumor patients treated by chemotherapy and the bone marrow microenvironment protecting effect in mice.Methods: Patients of non-small-cell pulmonary, mammary, gastric or intestinal cancer, who were ready for receiving re-treatment of chemotherapy, were enrolled and divided into 4 groups randomly. The 28 cases in SHSBG group A received chemotherapy combined with SHSBG; the 27 in the SHSBG group B received chemotherapy alone at first, and SHSBG was added when their peripheral white blood cell (WBC) count lowered to ＜4×109/L; the 33 in control group A and 24 in control group B were treated by the method similar to that applied to SHSBG group A and B respectively but with Rubidate instead of SHSBG. Experimental study of electron microscopic observation on bone marrow ultrastructure in mice was also conducted.Results: The total leukocyte increasing effective rate occurred in SHSBG group A and B was 75.00% and 88.89%, while in control group A and B, 54.55% and 58.33% respectively, and the difference between the SHSBG groups and the control groups was significant (P<0.01). Experimental study showed that SHSBG has good bone marrow hematopoietic microenvironment protecting and improving effect in mice.Conclusion: SHSBG has obvious protecting and treating effect on chemotherapy induced bone marrow suppression in tumor patients.展开更多
Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)microenvironment.Curre...Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)microenvironment.Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion.Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents.Recently,monoclonal antibodies,bispecific antibodies,and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses.While current MM therapies have markedly extended patient survival,acquired drug resistance inevitably emerges and drives disease progression.The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies.The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies.Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance.Here,we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance.Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.展开更多
Multiple myeloma(MM)is a type of hematological cancer that occurs when B cells become malignant.Various drugs such as proteasome inhibitors,immunomodulators,and compounds that cause DNA damage can be used in the treat...Multiple myeloma(MM)is a type of hematological cancer that occurs when B cells become malignant.Various drugs such as proteasome inhibitors,immunomodulators,and compounds that cause DNA damage can be used in the treatment of MM.Autophagy,a type 2 cell death mechanism,plays a crucial role in determining the fate of B cells,either promoting their survival or inducing cell death.Therefore,autophagy can either facilitate the progression or hinder the treatment of MM disease.In this review,autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response(UPR),bone marrow microenvironment(BMME),drug resistance,hypoxia,DNA repair and transcriptional regulation,and apoptosis.The genes that are effective in each mechanism and research efforts on this subject were discussed in detail.Signaling pathways targeted by new drugs to benefit from autophagy in MM disease were covered.The efficacy of drugs that regulate autophagy in MM was examined,and clinical trials on this subject were included.Consequently,among the autophagy mechanisms that are effective in MM,the most suitable ones to be used in the treatment were expressed.The importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was emphasized.Ultimately,this review aims to provide a comprehensive overview of MM disease,encompassing autophagy mechanisms,drugs,clinical studies,and further studies.展开更多
基金Supported by a grant from National Scaling Height Program, China (No. 95-zhuan-10)
文摘Objective： The aim of the study was to investigate the expression pattern of hematopoietic transcription factor GATA-1, -2 and -3 genes in leukemic bone marrow （BM） micreenvironment [including bone marrow stremal cells （BMSCs） and BM hematopoietic cells]. Methods： Mononuclear cells were isolated from BM of patients with acute myeloid leukemia （AML）, chronic myelogenous leukemia （CML）, or acute lymphoblasUc leukemia （ALL）. Adherent cells （BMSCs） and nonadherent ceils （BM hematopoietic cells） were collected after long-term culture in vitro. The semi-quantitative expression levels of GATA genes in the BMSCs or BM hematopoietic cells from patients with leukemia were analyzed by using RT-PCR-ELISA and com- pared with normal controls. Results： The expression level of GATA-1 gene in the BMSCs from CML group was significantly lower than that of the normal controls. The expression level of GATA-3 gene in the BMSCs from ALL was higher than that of the normal controls, but that from CML was lower than the normal controls. Dominant expression of GATA-3 gene was found in the normal BM hematopoietic cells. The dominant expression of GATA-2 gene was found in the normal BMSCs and the BMSCs from CML, whereas the dominant expression of GATA-3 gene was detected in the BMSCs from AML. Conclusion： GATA-1, -2 and -3 genes might play a role in hematopoiesis regulation in leukemia, and the changes of expression pattern of GATA genes might influence the hematopoiesis in BM microenvironment and relate to the pathogenesis and development of leukemia.
文摘In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment,acute myeloid leukemia(AML)cells continuously adjust their metabolic state.To meet the biochemical demands of their increased proliferation,AML cells strongly depend on mitochondrial oxidative phosphorylation(OXPHOS).Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation(FAO),which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance.For targeting these metabolic vulnerabilities of AML cells,inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential.Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells,enabling them to acquire resistance against OXPHOS and FAO inhibitors.These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors.Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.
基金Supported by The“Instituto de Salud Carlos III,No.PI22/00264A Predoctoral Program in Biomedicine from The University of Cantabria and The Instituto de Investigación Valdecilla-IDIVAL(Alberto González-González and Daniel García-Sánchez),No.PREVAL19/02,and No.PREVAL20/01“Investigo Program”,part of the“Plan Nacional de Recuperación,Transformación y Resiliencia”from The Spanish Government(Mónica del Dujo-Gutiérrez).
文摘Multiple myeloma(MM)is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow(BM).The interaction between MM cells and the BM microenvironment,and specifically BM mesenchymal stem cells(BM-MSCs),has a key role in the pathophysiology of this disease.Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs,aiding the progression of this hematological tumor.The relation of MM cells with the resident BM-MSCs is a two-way interaction.MM modulate the behavior of BM-MSCs altering their expression profile,proliferation rate,osteogenic potential,and expression of senescence markers.In turn,modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression.The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs,long non-coding RNAs or other molecules.However,the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes.Thus,understanding the way this communication works and developing strategies to interfere in the process,would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.
文摘Bone marrow(BM)microenvironment regulates and supports the production of blood cells which are necessary to maintain homeostasis.In analogy to normal hematopoiesis,leukemogenesis is originated from leukemic stem cells(LSCs)which gives rise to more differentiated malignant cells.Leukemia cells occupy BM niches and reconstruct them to support leukemogenesis.The abnormal BM niches are the main sanctuary of LSCs where they can evade chemotherapy-induced death and acquire drug resistance.In this review,we focus on the protective effects of BM niche cells on acute lymphoblastic leukemia cells.
文摘Objective:To evaluate the effect of ligust razine on bone marrow hematopoietic microenvironment and signal transduction in irradiation injured mice.Methods:After being irradiated by 6.0 Gy 60 Co γ -ray, the mice in the ligustrazine group were orally given ligustrazine 4 mg/mouse twice a day to the end of the experiment. For the control group, normal saline was given instead of ligustrazine and the mice in the normal group was untreated. The mice were sacrificed separately on the 3rd, 7th and 14th day after radiation, bone marrow of them was taken and m anaged as follows:(1) Make stromal cell culture to observe the growth state and the expression of focal adhesion kinase (FAK) of the cells; (2) Make the bo ne marrow section to examine the pathological and immunohistochemistry changes, including the expression of fetal liver kinase-1 (Flk-1) and F VIII :RAg. The data were recorded and compared among groups.Results:After radiation, the hematopoietic cells in bo ne marrow decreased and the micro vessels dilated and congested with bleeding; bone mar row became thinner, red colored with cells of irregular shape and few cells adhere to the bottom of culture flask. These changes began to recover at the 7th day and approached to normal within 2 weeks. The recovery was better, earlier and quick er in the ligustrazine group than that in the control group. The expression lev els of Flk-1 decreased significantly.Conclusion: Ligustrazine could promote the recovery of hematopoietic function of radiation damaged bone marrow, the mechanisms might be through imp roving the microenvironment and signal transduction path for recovery.
基金Meyer LK is supported by a Genentech Foundation Fellowship Award.Hermiston ML is supported by the National Cancer Institute Grant R01 CA193776the Buster Posey Family Foundation,the Campini Foundation,and the Pepp Family Foundation.
文摘Acute lymphoblastic leukemia(ALL)is a malignancy of immature lymphoid cells that arises due to clonal expansion of cells that undergo developmental arrest and acquisition of pathogenic mutations.With the introduction of intensive multi-agent chemotherapeutic regimens,survival rates for ALL have improved dramatically over the past several decades,though survival rates for adult ALL continue to lag behind those of pediatric ALL.Resistance to chemotherapy remains a significant obstacle in the treatment of ALL,and chemoresistance due to molecular alterations within ALL cells have been described.In addition to these cell-intrinsic factors,the bone marrow microenvironment has more recently been appreciated as a cell-extrinsic mediator of chemoresistance,and it is now known that stromal cells within the bone marrow microenvironment,through direct cell-cell interactions and through the release of lymphoid-acting soluble factors,contribute to ALL pathogenesis and chemoresistance.This review discusses mechanisms of chemoresistance mediated by factors within the bone marrow microenvironment and highlights novel therapeutic strategies that have been investigated to overcome chemoresistance in this context.
基金ThisprojectwassupportedbyagrantfromtheNationalNatu ralScienceFoundationofChina (No .39870 92 6 )
文摘To study the expression of the bFGF and its receptor in the mouse bone marrow by treatment with acute radioactive injury and Ligustrazine, 56 mice were divided into 3 groups: normal group, radiation injured group and Ligustrazine group. After irradiation by 6.0 Gy 60 Co γ ray, each mouse was orally given 0.1 ml Ligustrazine twice a day for 13 days in Ligustrazine group, and each mouse in radiation injured group was orally given equal amount of saline. On the 3rd, 7th, 14th day after irradiation, bone marrow mono nuclear cells (BMMNC) were counted, and the expression levels of bFGF and bFGFR in bone marrow were evaluated by immunohistochemistry and flow cytometry analysis respectively. On the 3rd, 7th, 14th day after irradiation, expression of bFGF in bone marrow were significantly lower than in normal group ( P <0.05 or P <0.01). Expressions of bFGF and bFGFR were much higher in Ligustrazine treated group than that in the control group ( P <0.05 or P <0.01). Ligustrazine potentiate the expression of bFGF and bFGFR in bone marrow MNC to recover the bone marrow hematopoiesis inductive microenvironment, which is one of the mechanisms by which Ligustrazine rebuild the bone marrow hematopoiesis after acute radioactive injury.
基金Supported by the "Ninth Five" Obligatory Budget of PLA. No. 96L045
文摘Objective: To explore the effect of gamma irradiation on nuclear factor-kappa B in cultured bone marrow stromal cells. Methods: Immunocytochemistry, Western blot and electrophoretic mobility shift assay (EMSA) were used. Results: The expression of NF-kB in cultured mouse bone marrow stromal cells (BM-SCs) on the level of protein was elevated after exposure to 60Co in the dosage of 8. 0 Gy with the use of im-munocytochemistry and Western blot. The activity of nuclear factor-kappa B in cultured BMSCs was significantly increased after exposure to gamma irradiation by using EMSA. The activity peak was at the 4th h after irradiation. Conclusion: Our results suggest that the activation of nuclear factor-kappa B in the BMSCs after irradiation may be involved in the protection of BMSCs against apoptosis and in the recovery of hematopoiesis after radiation.
基金supported by the National Key R&D Program of China(2022YFA1103300)the National Natural Science Foundation of China(81873424,81570097)+2 种基金the Natural Science Foundation of Chongqing Innovation Group Science Program(cstc2021jcyjcxttX0001)Clinical Medical Research Project of Army Medical University(2018XLC1006)and Translational Research Grant of NCRCH(2020ZKZC02).
文摘Background: Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. Methods: Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca^(2+)-related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. Results: Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca ^(2+ )is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. Conclusions: Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy.
基金National Natural Science Foundation of China(81890990)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-019)+1 种基金Chinese Academy of Medical Sciences Fundamental Research Funds for Central Research Institutes(3332021093)Haihe Laboratory of Cell Ecosystem Innovation Fund(HH22KYZX0016).
文摘Leukemia stem cells in acute myeloid leukemia(AML)can persist within unique bone marrow niches similar to those of healthy hematopoietic stem cells and resist chemotherapy.In the context of AML,endothelial cells(ECs)are crucial components of these niches that appear to promote malignant expansion despite treatment.To better understand these interactions,we developed a real-time cell cycle-tracking mouse model of AML(Fucci-MA9)with an aim of unraveling why quiescent leukemia cells are more resistant to chemotherapy than cycling cells and proliferate during disease relapse.We found that quiescent leukemia cells were more prone to escape chemotherapy than cycling cells,leading to relapse and proliferation.Importantly,post-chemotherapy resting leukemia cells tended to localize closer to blood vessels.Mechanistically,after chemotherapy,resting leukemia cells interacted with ECs,promoting their adhesion and anti-apoptotic capacity.Further,expression analysis of ECs and leukemia cells during AML,after chemotherapy,and after relapse revealed the potential of suppressing the post-chemotherapy inflammatory response to regulate the functions of leukemia cells and ECs.These findings highlight the role of leukemia cells in evading chemotherapy by seeking refuge near blood vessels and provide important insights and directions for future AML research and treatment.
文摘To observe the leucocyte increasing effect of Shuanghuang Shengbai Granule (SHSBG) in tumor patients treated by chemotherapy and the bone marrow microenvironment protecting effect in mice.Methods: Patients of non-small-cell pulmonary, mammary, gastric or intestinal cancer, who were ready for receiving re-treatment of chemotherapy, were enrolled and divided into 4 groups randomly. The 28 cases in SHSBG group A received chemotherapy combined with SHSBG; the 27 in the SHSBG group B received chemotherapy alone at first, and SHSBG was added when their peripheral white blood cell (WBC) count lowered to ＜4×109/L; the 33 in control group A and 24 in control group B were treated by the method similar to that applied to SHSBG group A and B respectively but with Rubidate instead of SHSBG. Experimental study of electron microscopic observation on bone marrow ultrastructure in mice was also conducted.Results: The total leukocyte increasing effective rate occurred in SHSBG group A and B was 75.00% and 88.89%, while in control group A and B, 54.55% and 58.33% respectively, and the difference between the SHSBG groups and the control groups was significant (P<0.01). Experimental study showed that SHSBG has good bone marrow hematopoietic microenvironment protecting and improving effect in mice.Conclusion: SHSBG has obvious protecting and treating effect on chemotherapy induced bone marrow suppression in tumor patients.
基金supported by NIH R01(5R01AI139141 to JJD),University Hospitals Cleveland Medical Center/Seidman Cancer Center,and the Case Comprehensive Cancer Center.
文摘Multiple myeloma(MM)remains an incurable,genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow(BM)microenvironment.Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion.Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents.Recently,monoclonal antibodies,bispecific antibodies,and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses.While current MM therapies have markedly extended patient survival,acquired drug resistance inevitably emerges and drives disease progression.The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies.The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies.Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance.Here,we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance.Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.
基金funded by TUBITAK(Turkish Scientific and Technological Council)grant number 121C417.
文摘Multiple myeloma(MM)is a type of hematological cancer that occurs when B cells become malignant.Various drugs such as proteasome inhibitors,immunomodulators,and compounds that cause DNA damage can be used in the treatment of MM.Autophagy,a type 2 cell death mechanism,plays a crucial role in determining the fate of B cells,either promoting their survival or inducing cell death.Therefore,autophagy can either facilitate the progression or hinder the treatment of MM disease.In this review,autophagy mechanisms that may be effective in MM cells were covered and evaluated within the contexts of unfolded protein response(UPR),bone marrow microenvironment(BMME),drug resistance,hypoxia,DNA repair and transcriptional regulation,and apoptosis.The genes that are effective in each mechanism and research efforts on this subject were discussed in detail.Signaling pathways targeted by new drugs to benefit from autophagy in MM disease were covered.The efficacy of drugs that regulate autophagy in MM was examined,and clinical trials on this subject were included.Consequently,among the autophagy mechanisms that are effective in MM,the most suitable ones to be used in the treatment were expressed.The importance of 3D models and microfluidic systems for the discovery of new drugs for autophagy and personalized treatment was emphasized.Ultimately,this review aims to provide a comprehensive overview of MM disease,encompassing autophagy mechanisms,drugs,clinical studies,and further studies.
