Objective: To investigate the therapeutic effect of applying venetoclax combined with demethylating drugs in treating patients with acute myeloid leukemia (AML). Methods: Eighty cases of AML patients treated with vene...Objective: To investigate the therapeutic effect of applying venetoclax combined with demethylating drugs in treating patients with acute myeloid leukemia (AML). Methods: Eighty cases of AML patients treated with venetoclax combined with demethylating drugs in our hospital were selected from March 2021 to March 2024, including 40 cases of primary treatment patients and 40 cases of relapsed and refractory patients. The efficacy and safety of the combined drug therapy was analyzed. Results: The primary treatment group was presented with a complete remission (CR) rate of 40.5%, partial remission (PR) rate of 47.50%, no response (NR) rate of 12.50%, and a remission rate of 87.50%. The relapsed- refractory group was presented with a CR rate of 37.50%, PR rate of 42.50%, NR rate of 17.50%, and a remission rate of 87.50%. There was no statistical significance between the groups (P > 0.05). The hematological adverse reactions of the combined treatment for AML were leukopenia and the non-hematological adverse reactions were mainly infections, with an incidence rate of 87.50%. Conclusion: The efficacy of venetoclax combined with demethylating drugs in AML was remarkable and the treatment regimen can be adjusted according to the treatment-resistant response.展开更多
In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable on...In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable oncoprotein for degradation in APL.Elucidating the mechanism regulating the stability of PML/RARαmay help to degrade PML/RARαand eradicate APL cells.Here,we describe a deubiquitinase(DUB)-involved regulatory mechanism for the maintenance of PML/RARαstability and develop a novel pharmacological approach to degrading PML/RARαby inhibiting DUB.We utilized a DUB siRNA library to identify the ovarian tumor protease(OTU)family member deubiquitinase YOD1 as a critical DUB of PML/RARα.Suppression of YOD1 promoted the degradation of PML/RARα,thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice.Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I(G5)as the first YOD1 pharmacological inhibitor.As expected,G5 notably degraded PML/RARαprotein and eradicated APL,particularly drug-resistant APL cells.Importantly,G5 also showed a strong killing effect on primary patient-derived APL blasts.Overall,our study not only reveals the DUB-involved regulatory mechanism on PML/RARαstability and validates YOD1 as a potential therapeutic target for APL,but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL,particularly drug-resistant APL treatment.展开更多
FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid l...FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.展开更多
Although complete remission could be achieved in about 60%–70%of acute myeloid leukemia(AML)patients after conventional chemotherapy,relapse and the state of being refractory to treatment remain the main cause of dea...Although complete remission could be achieved in about 60%–70%of acute myeloid leukemia(AML)patients after conventional chemotherapy,relapse and the state of being refractory to treatment remain the main cause of death.In addition,there is a great need for less intensive regimens for all medically frail patients(both due to age/comorbidity and treatment-related).Immune therapy anticipates improved prognosis and reduced toxicities,which may offer novel therapeutic rationales.However,one of the major difficulties in developing immune therapies against AML is that the target antigens are also significantly expressed on healthy hematopoietic stem cells;B-cell malignancies are different because CD20/CD19/healthy B-cells are readily replaceable.Only the anti-CD33 antibody-drug conjugate gemtuzumab-ozogamicin is approved by the FDA for AML.Thus,drug development remains extremely active,although it is still in its infancy.This review summarizes the clinical results of immune therapeutic agents for AML,such as antibody-based drugs,chimeric antigen receptor therapy,checkpoint inhibitors,and vaccines.展开更多
S-dimethylarsino-glutathione(ZIO-101,darinaparsin®)exhibits broader antitumor activity and less toxicity than arsenic trioxide(ATO),a clinically used drug for acute promyelocytic leukemia(APL)treatment.However,th...S-dimethylarsino-glutathione(ZIO-101,darinaparsin®)exhibits broader antitumor activity and less toxicity than arsenic trioxide(ATO),a clinically used drug for acute promyelocytic leukemia(APL)treatment.However,the mechanisms of action underlying antileukemia activities of ZIO-101 remain largely unknown.Herein,by integrating dynamic transcriptomic analysis and biochemical characterizations,we for the first time delineated that ZIO-101 exerted antiproliferative effects against leukemia cells via activating ferroptosis pathway,a newly discovered iron-dependent programmed cell death,at the early stage,as evidenced by abnormally elevated intracellular iron contents and lipid peroxidation.We further demonstrated that silencing heme oxygenase 1(HMOX1),an important iron homeostasis-related gene,effectively attenuated ferroptosis induced by ZIO-101,with iron accumulation and lipid peroxidation being significantly alleviated.Significantly,we discovered that ZIO-101 and kinase inhibitors(Dasatinib/Dactolisib)could synergistically kill leukemia cells,with a combination index of<1.0 under all the tested drug concentrations.Our findings regarding the ferroptosis-mediated antileukemia activity of ZIO-101,based on the dynamic and temporal transcriptomic analysis,provide promising approaches to combat drug-resistant leukemia by combining ZIO-101 with kinase inhibitors.The methodology may be further exploited for uncovering the modes of action of other drugs.展开更多
本研究采用回顾性方法分析大剂量甲氨喋呤(HD-MTX)为主的HD-MTX-CF+VDT方案在儿童急性淋巴细胞性白血病(ALL)髓外防治中的作用及意义,并分析HD-MTX的毒副作用及动态MTX血药浓度监测在该方案中的重要作用,以避免或减轻HD-MTX的毒副作用,...本研究采用回顾性方法分析大剂量甲氨喋呤(HD-MTX)为主的HD-MTX-CF+VDT方案在儿童急性淋巴细胞性白血病(ALL)髓外防治中的作用及意义,并分析HD-MTX的毒副作用及动态MTX血药浓度监测在该方案中的重要作用,以避免或减轻HD-MTX的毒副作用,及时调整亚叶酸钙(CF)的解救剂量或必要时与以血浆置换,保证化疗的安全性及降低患儿骨髓外复发的几率。对180例ALL患儿先后进行380次HD-MTX-CF+VDT方案的髓外防治,其中诱导缓解期患儿122例,维持期患儿58例;低危组68例、中危组80例、高危组32例。结果表明:HD-MTX的毒副作用包括皮肤黏膜损害、胃肠道反应、肝功能及肾功能受累、发热、骨髓抑制、感染、过敏反应、极少数心肌损害等,占36.3%,均为可逆性损害。本组患儿出现MTX排泄延迟者110例,24小时MTX浓度>10μm o l/L者3例、44小时>1.0μm o l/L者50例、68小时>0.1μm o l/L者57例,以合理调整CF解救剂量及对症治疗保护脏器功能均使MTX血药浓度降到0.1μm o l/L以下的无毒浓度,1例发生肾功能不全并治愈。结论:以HD-MTX为主的髓外防治方案对提高ALL患儿长期缓解及无事件生存率至关重要,但其相关副作用及风险性也随着MTX的剂量增大而增加,且MTX在体内代谢程度存在较大个体差异,因而在治疗过程中动态监测MTX的血药浓度,指导适时适量的CF解救是HD-MTX方案能够安全有效实施的前提和保障。展开更多
文摘Objective: To investigate the therapeutic effect of applying venetoclax combined with demethylating drugs in treating patients with acute myeloid leukemia (AML). Methods: Eighty cases of AML patients treated with venetoclax combined with demethylating drugs in our hospital were selected from March 2021 to March 2024, including 40 cases of primary treatment patients and 40 cases of relapsed and refractory patients. The efficacy and safety of the combined drug therapy was analyzed. Results: The primary treatment group was presented with a complete remission (CR) rate of 40.5%, partial remission (PR) rate of 47.50%, no response (NR) rate of 12.50%, and a remission rate of 87.50%. The relapsed- refractory group was presented with a CR rate of 37.50%, PR rate of 42.50%, NR rate of 17.50%, and a remission rate of 87.50%. There was no statistical significance between the groups (P > 0.05). The hematological adverse reactions of the combined treatment for AML were leukopenia and the non-hematological adverse reactions were mainly infections, with an incidence rate of 87.50%. Conclusion: The efficacy of venetoclax combined with demethylating drugs in AML was remarkable and the treatment regimen can be adjusted according to the treatment-resistant response.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81973354 to Meidan Ying)China Postdoctoral Science Foundation(No.2020T130593 to Xuejing Shao)Leading Talent of“Ten Thousand Plan”-National High-Level Talents Special Support Plan and the Fundamental Research Funds for the Central Universities(China).
文摘In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable oncoprotein for degradation in APL.Elucidating the mechanism regulating the stability of PML/RARαmay help to degrade PML/RARαand eradicate APL cells.Here,we describe a deubiquitinase(DUB)-involved regulatory mechanism for the maintenance of PML/RARαstability and develop a novel pharmacological approach to degrading PML/RARαby inhibiting DUB.We utilized a DUB siRNA library to identify the ovarian tumor protease(OTU)family member deubiquitinase YOD1 as a critical DUB of PML/RARα.Suppression of YOD1 promoted the degradation of PML/RARα,thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice.Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I(G5)as the first YOD1 pharmacological inhibitor.As expected,G5 notably degraded PML/RARαprotein and eradicated APL,particularly drug-resistant APL cells.Importantly,G5 also showed a strong killing effect on primary patient-derived APL blasts.Overall,our study not only reveals the DUB-involved regulatory mechanism on PML/RARαstability and validates YOD1 as a potential therapeutic target for APL,but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL,particularly drug-resistant APL treatment.
基金Supported by the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program(to Chng WJ)NMRC Clinician-Scientist IRG Grant,No.CNIG11nov38(to Zhou J)+1 种基金supported by NMRC Clinician Scientist Investigator awardsupported by the RNA Biology Center at CSI Singapore,NUS,from funding by the Singapore Ministry of Education’s Tier 3 grants,No.MOE2014-T3-1-006
文摘FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.
基金Tianjin Health Science and Technology Project and Natural Science Foundation of Xinjiang Autonomous Region(2022D01A09).
文摘Although complete remission could be achieved in about 60%–70%of acute myeloid leukemia(AML)patients after conventional chemotherapy,relapse and the state of being refractory to treatment remain the main cause of death.In addition,there is a great need for less intensive regimens for all medically frail patients(both due to age/comorbidity and treatment-related).Immune therapy anticipates improved prognosis and reduced toxicities,which may offer novel therapeutic rationales.However,one of the major difficulties in developing immune therapies against AML is that the target antigens are also significantly expressed on healthy hematopoietic stem cells;B-cell malignancies are different because CD20/CD19/healthy B-cells are readily replaceable.Only the anti-CD33 antibody-drug conjugate gemtuzumab-ozogamicin is approved by the FDA for AML.Thus,drug development remains extremely active,although it is still in its infancy.This review summarizes the clinical results of immune therapeutic agents for AML,such as antibody-based drugs,chimeric antigen receptor therapy,checkpoint inhibitors,and vaccines.
基金supported by the Research Grants Council of Hong Kong(nos.17307017 and R7070-18)the Innovation and Technology Commission of Hong Kong(no.ITS/124/17)the University of Hong Kong(for a scholarship to XHX).
文摘S-dimethylarsino-glutathione(ZIO-101,darinaparsin®)exhibits broader antitumor activity and less toxicity than arsenic trioxide(ATO),a clinically used drug for acute promyelocytic leukemia(APL)treatment.However,the mechanisms of action underlying antileukemia activities of ZIO-101 remain largely unknown.Herein,by integrating dynamic transcriptomic analysis and biochemical characterizations,we for the first time delineated that ZIO-101 exerted antiproliferative effects against leukemia cells via activating ferroptosis pathway,a newly discovered iron-dependent programmed cell death,at the early stage,as evidenced by abnormally elevated intracellular iron contents and lipid peroxidation.We further demonstrated that silencing heme oxygenase 1(HMOX1),an important iron homeostasis-related gene,effectively attenuated ferroptosis induced by ZIO-101,with iron accumulation and lipid peroxidation being significantly alleviated.Significantly,we discovered that ZIO-101 and kinase inhibitors(Dasatinib/Dactolisib)could synergistically kill leukemia cells,with a combination index of<1.0 under all the tested drug concentrations.Our findings regarding the ferroptosis-mediated antileukemia activity of ZIO-101,based on the dynamic and temporal transcriptomic analysis,provide promising approaches to combat drug-resistant leukemia by combining ZIO-101 with kinase inhibitors.The methodology may be further exploited for uncovering the modes of action of other drugs.
文摘本研究采用回顾性方法分析大剂量甲氨喋呤(HD-MTX)为主的HD-MTX-CF+VDT方案在儿童急性淋巴细胞性白血病(ALL)髓外防治中的作用及意义,并分析HD-MTX的毒副作用及动态MTX血药浓度监测在该方案中的重要作用,以避免或减轻HD-MTX的毒副作用,及时调整亚叶酸钙(CF)的解救剂量或必要时与以血浆置换,保证化疗的安全性及降低患儿骨髓外复发的几率。对180例ALL患儿先后进行380次HD-MTX-CF+VDT方案的髓外防治,其中诱导缓解期患儿122例,维持期患儿58例;低危组68例、中危组80例、高危组32例。结果表明:HD-MTX的毒副作用包括皮肤黏膜损害、胃肠道反应、肝功能及肾功能受累、发热、骨髓抑制、感染、过敏反应、极少数心肌损害等,占36.3%,均为可逆性损害。本组患儿出现MTX排泄延迟者110例,24小时MTX浓度>10μm o l/L者3例、44小时>1.0μm o l/L者50例、68小时>0.1μm o l/L者57例,以合理调整CF解救剂量及对症治疗保护脏器功能均使MTX血药浓度降到0.1μm o l/L以下的无毒浓度,1例发生肾功能不全并治愈。结论:以HD-MTX为主的髓外防治方案对提高ALL患儿长期缓解及无事件生存率至关重要,但其相关副作用及风险性也随着MTX的剂量增大而增加,且MTX在体内代谢程度存在较大个体差异,因而在治疗过程中动态监测MTX的血药浓度,指导适时适量的CF解救是HD-MTX方案能够安全有效实施的前提和保障。
