Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoi...Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation.Genes integral to critical cellular processes such as epigenetic regulation,DNA damage response,and inflammation frequently carry these mutations.Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions.Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis.Here,we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH,as well as look forward to future related studies,so as to provide valuable references for future research and clinical practice.展开更多
Aging-elevated DNMT3A R882H-driven clonal hematopoiesis(CH)is a risk factor for myeloid malignancies remission and overall survival.Although some studies were conducted to investigate this phenomenon,the exact mechani...Aging-elevated DNMT3A R882H-driven clonal hematopoiesis(CH)is a risk factor for myeloid malignancies remission and overall survival.Although some studies were conducted to investigate this phenomenon,the exact mechanism is still under debate.In this study,we observed that DNMT3 A R878 H bone marrow cells(human allele:DNMT3 A R882 H)displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult.DNMT3 A R878 H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation,especially TNFa insults.Mechanistically,we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878 H cells in response to proliferation stress and TNFa insults.Briefly,we elucidated the molecular mechanism driving DNMT3 A R878 H-based clonal hematopoiesis,which raises clinical value for treating DNMT3 A R882 H-driven clonal hematopoiesis and myeloid malignancies with aging.展开更多
We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations(GCPs).This patient ...We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations(GCPs).This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments,with each recurrence occurring 7-8 wk from a GCP.After his third recurrence,he was prescribed successive treatment with rifampicin,berberine,and monthly administered GCP for 4 mo,and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy,and eventually died of septic shock.Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis.From the treatment process and laboratory investigations,it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state.Incorporation of rifampicin,berberine,and monthly GCP into cyclosporine can enhance the immunosuppressive effect.In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure,the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.展开更多
Myeloproliferative neoplasms(MPNs)are a heterogeneous group of hematologic malignancies characterized by an abnormal proliferation of cells of the myeloid lineage.Affected individuals are at increased risk for cardiov...Myeloproliferative neoplasms(MPNs)are a heterogeneous group of hematologic malignancies characterized by an abnormal proliferation of cells of the myeloid lineage.Affected individuals are at increased risk for cardiovascular and thrombotic events.Myocardial infarction(MI)may be one of the earliest clinical manifestations of MPNs or may be a thrombotic complication that develops during the natural course of the disease.In the present review,we examine the epidemiology,pathogenesis,clinical presentation,and management of MI in MPNs based on the available literature.Moreover,we review potential biomarkers that could mediate the MI-MPNs crosstalk,from classical biochemical tests,e.g.,lactate dehydrogenase,creatine kinase and troponins,to pro-inflammatory cytokines,oxidative stress markers,and clonal hematopoiesis.展开更多
Acute myeloid leukemia(AML)has been shown to undergo multiple acquired mutations in hematopoietic cell lineages over years before becoming clinically apparent.The early stage of AML(before it becomes clinically recogn...Acute myeloid leukemia(AML)has been shown to undergo multiple acquired mutations in hematopoietic cell lineages over years before becoming clinically apparent.The early stage of AML(before it becomes clinically recognizable)may be characterized by acquisition of some,but not all,leukemia-related somatic mutations in hematopoietic stem cells(HSCs).The physiological roles of these mutations remain puzzling.These HSCs have been termed as preleukemic HSCs.However,those frequent acquired somatic mutations are also found in healthy aging adults,namely,“age-related clonal hematopoiesis.”Multiple studies have demonstrated that the preleukemic HSCs survive through chemotherapy and then contribute to the relapse and the development of de novo AML.Whether preleukemic HSCs should be targeted or whether a preventive therapy should be considered for those individuals remains to be determined.This article aims to shed light on this special subject and to discuss the roles of preleukemic HSCs in leukemogenesis.展开更多
基金Supported by a grant from the National Natural Science Founda-tion of China(no.82200319).
文摘Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation.Genes integral to critical cellular processes such as epigenetic regulation,DNA damage response,and inflammation frequently carry these mutations.Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions.Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis.Here,we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH,as well as look forward to future related studies,so as to provide valuable references for future research and clinical practice.
基金the Beijing Advanced Innovation Center for Structural Biology and the Tsinghua-Peking Center for Life Sciences for facility and financial supportsupported by grant numbers 2018YFA0800200,2017YFA0104000,91849106,Z200022,Z181100001818005 and 81870118 to Jianwei Wang from the National Key R&D Program of China or the Beijing Municipal Science&Technology Commission and the National Natural Science Foundation of China。
文摘Aging-elevated DNMT3A R882H-driven clonal hematopoiesis(CH)is a risk factor for myeloid malignancies remission and overall survival.Although some studies were conducted to investigate this phenomenon,the exact mechanism is still under debate.In this study,we observed that DNMT3 A R878 H bone marrow cells(human allele:DNMT3 A R882 H)displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult.DNMT3 A R878 H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation,especially TNFa insults.Mechanistically,we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878 H cells in response to proliferation stress and TNFa insults.Briefly,we elucidated the molecular mechanism driving DNMT3 A R878 H-based clonal hematopoiesis,which raises clinical value for treating DNMT3 A R882 H-driven clonal hematopoiesis and myeloid malignancies with aging.
文摘We previously reported a serendipitous finding from a patient with refractory severe aplastic anemia who had gotten an unexpected hematological response to treatment with gut-cleansing preparations(GCPs).This patient experienced three recurrences over the ensuing one year of intermittent GCP treatments,with each recurrence occurring 7-8 wk from a GCP.After his third recurrence,he was prescribed successive treatment with rifampicin,berberine,and monthly administered GCP for 4 mo,and he developed an erythroid proliferative neoplasma and an overwhelming enteropathy,and eventually died of septic shock.Laboratory investigations had validated the resolution of myelosuppression and the appearance of malignant clonal hematopoiesis.From the treatment process and laboratory investigations,it is reasonably inferred that the engagement of gut inflammation is critically required in sustaining the overall pathophysiology of acquired aplastic anemia probably by creating a chronic inflammatory state.Incorporation of rifampicin,berberine,and monthly GCP into cyclosporine can enhance the immunosuppressive effect.In a subgroup of acquired aplastic anemia patients whose pathogenesis is associated with genotoxic exposure,the suppressed normal hematopoiesis may result from the bystander insult that is mediated by the soluble inflammatory cytokines generated in response to the immunogenic products of damaged hematopoietic cells in the context of chronic inflammatory state and may offer a protective antineoplastic mechanism against malignant proliferation.
文摘Myeloproliferative neoplasms(MPNs)are a heterogeneous group of hematologic malignancies characterized by an abnormal proliferation of cells of the myeloid lineage.Affected individuals are at increased risk for cardiovascular and thrombotic events.Myocardial infarction(MI)may be one of the earliest clinical manifestations of MPNs or may be a thrombotic complication that develops during the natural course of the disease.In the present review,we examine the epidemiology,pathogenesis,clinical presentation,and management of MI in MPNs based on the available literature.Moreover,we review potential biomarkers that could mediate the MI-MPNs crosstalk,from classical biochemical tests,e.g.,lactate dehydrogenase,creatine kinase and troponins,to pro-inflammatory cytokines,oxidative stress markers,and clonal hematopoiesis.
基金This work was supported by grants from the Ministry of Science and Technology of China(2016YFA0100600,2017YFA0103400)the National Natural Science Foundation of China(81861148029,81730006,81922002,81870086)CAMS Initiative for Innovative Medicine(2019-I2M-1-006,2017-I2M-3-009).
文摘Acute myeloid leukemia(AML)has been shown to undergo multiple acquired mutations in hematopoietic cell lineages over years before becoming clinically apparent.The early stage of AML(before it becomes clinically recognizable)may be characterized by acquisition of some,but not all,leukemia-related somatic mutations in hematopoietic stem cells(HSCs).The physiological roles of these mutations remain puzzling.These HSCs have been termed as preleukemic HSCs.However,those frequent acquired somatic mutations are also found in healthy aging adults,namely,“age-related clonal hematopoiesis.”Multiple studies have demonstrated that the preleukemic HSCs survive through chemotherapy and then contribute to the relapse and the development of de novo AML.Whether preleukemic HSCs should be targeted or whether a preventive therapy should be considered for those individuals remains to be determined.This article aims to shed light on this special subject and to discuss the roles of preleukemic HSCs in leukemogenesis.
