With the recent ongoing autumn/winter 2022 COVID-19 wave and the adjustment of public health control measures,there have been widespread SARS-CoV-2 infections in Chinese mainland.Here we have analyzed 369 viral genome...With the recent ongoing autumn/winter 2022 COVID-19 wave and the adjustment of public health control measures,there have been widespread SARS-CoV-2 infections in Chinese mainland.Here we have analyzed 369 viral genomes from recently diagnosed COVID-19 patients in Shanghai,identifying a large number of sublineages of the SARS-CoV-2 Omicron family.Phylogenetic analysis,coupled with contact history tracing,revealed simultaneous community transmission of two Omicron sublineages dominating the infections in some areas of China(BA.5.2 mainly in Guangzhou and Shanghai,and BF.7 mainly in Beijing)and two highly infectious sublineages recently imported from abroad(XBB and BQ.1).Publicly available data from August 31 to November 29,2022 indicated an overall severe/critical case rate of 0.035%nationwide,while analysis of 5706 symptomatic patients treated at the Shanghai Public Health Center between September 1 and December 26,2022 showed that 20 cases(0.35%)without comorbidities progressed into severe/critical conditions and 153 cases(2.68%)with COVID-19-exacerbated comorbidities progressed into severe/critical conditions.These observations shall alert healthcare providers to place more resources for the treatment of severe/critical cases.Furthermore,mathematical modeling predicts this autumn/winter wave might pass through major cities in China by the end of the year,whereas some middle and western provinces and rural areas would be hit by the upcoming infection wave in mid-to-late January 2023,and the duration and magnitude of upcoming outbreak could be dramatically enhanced by the extensive travels during the Spring Festival(January 21,2023).Altogether,these preliminary data highlight the needs to allocate resources to early diagnosis and effective treatment of severe cases and the protection of vulnerable population,especially in the rural areas,to ensure the country’s smooth exit from the ongoing pandemic and accelerate socio-economic recovery.展开更多
The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic.Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earl...The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic.Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earlier infection histories during a SARS-CoV-2 outbreak in Shanghai in spring 2022.Compared to an earlier patient cohort infected by SARS-CoV-2 prototype strains in 2020,BA.2.2 infection led to distinct fluctuations of pathophysiological markers in the peripheral blood.In particular,severe/critical cases of COVID19 post BA.2.2 infection were associated with less pro-inflammatory macrophage activation and stronger interferon alpha response in the bronchoalveolar microenvironment.Importantly,the abnormal biomarkers were significantly subdued in individuals who had been immunized by 2 or 3 doses of SARS-CoV-2 prototypeinactivated vaccines,supporting the estimation of an overall 96.02% of protection rate against severe/critical disease in the 4854 cases in our BA.2.2 patient cohort with traceable vaccination records.Furthermore,even though age was a critical risk factor of the severity of COVID-19 post BA.2.2 infection,vaccination-elicited protection against severe/critical COVID-19 reached 90.15% in patients aged≥60 years old.Together,our study delineates the pathophysiological features of Omicron BA.2.2 sublineages and demonstrates significant protection conferred by prior prototype-based inactivated vaccines.展开更多
The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In ...The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In this study,based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins,we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1.This gene,hereby named LY6A,reversely overlaps with a lncRNA gene in the majority of exonic sequences.We found that LY6A is aberrantly expressed in pituitary tumors,but not in normal pituitary tissues,and may contribute to tumorigenesis.Similar to mouse Ly-6A/Sca-1,human LY6A is also upregulated by interferon,suggesting a conserved transcriptional regulatory mechanism between humans and mice.We cloned the full-length LY6A cDNA,whose encoded protein sequence,domain architecture,and exon‒intron structures are all well conserved with mouse Ly-6A/Sca-1.Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane.Collectively,these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.展开更多
“The rolling Yangtze River flows eastward,washingaway the heroes in its waves.”These words were written by a poet,Shen Yang,500years ago in his poem Immortal by the River.“Countlessevents of the past and present ar...“The rolling Yangtze River flows eastward,washingaway the heroes in its waves.”These words were written by a poet,Shen Yang,500years ago in his poem Immortal by the River.“Countlessevents of the past and present are all turned into laughterand conversation of the white-haired fishermen andwoodcutters.”展开更多
Methotrexate,etoposide,dexamethasone,and pegaspargase(MESA)with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma,nasal type(NKTCL).We explored the efficacy and...Methotrexate,etoposide,dexamethasone,and pegaspargase(MESA)with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma,nasal type(NKTCL).We explored the efficacy and safety of reduced-intensity,non-intravenous etoposide,dexamethasone,and pegaspargase(ESA)with sandwiched radiotherapy.This multicenter,randomized,phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China.Patients were randomly assigned(1:1)to receive ESA(pegaspargase 2,500 IU/m^(2)intramuscularly on day 1,etoposide 200 mg orally,and dexamethasone 40 mg orally on days 2–4)or MESA(methotrexate 1 g/m^(2)intravenously on day 1,etoposide 200 mg orally,and dexamethasone 40 mg orally on days 2–4,and pegaspargase 2,500 IU/m^(2)intramuscularly on day 5)regimen(four cycles),combined with sandwiched radiotherapy.展开更多
B-cell precursor acute lymphoblastic leukemia(BCP-ALL)is characterized by genetic alterations with high heterogeneity.Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed ...B-cell precursor acute lymphoblastic leukemia(BCP-ALL)is characterized by genetic alterations with high heterogeneity.Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology.Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes,such as DUX4 rearrangements,MEF2D rearrangements,ZNF384/ZNF362 rearrangements,NUTM1 rearrangements,BCL2/MYC and/or BCL6 rearrangements,ETV6-RUNX1-like gene expression,PAX5alt(diverse PAX5 alterations,including rearrangements,intragenic amplifications,or mutations),and hotspot mutations PAX5(p.Pro80Arg)with biallelic PAX5 alterations,IKZF1(p.Asn159Tyr),and ZEB2(p.His1038Arg).These molecular subtypes could be classified by gene expression patterns with RNA-seq technology.Refined molecular classification greatly improved the treatment strategy.Multiagent therapy regimens,including target inhibitors(e.g.,imatinib),immunomodulators,monoclonal antibodies,and chimeric antigen receptor T-cell(CAR-T)therapy,are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management.We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.展开更多
Since the outbreak of the COVID-19 pandemic in early December 2019,81174 confirmed cases and 3242 deaths have been reported in China as of March 19,2020.The Chinese people and government have contributed huge efforts ...Since the outbreak of the COVID-19 pandemic in early December 2019,81174 confirmed cases and 3242 deaths have been reported in China as of March 19,2020.The Chinese people and government have contributed huge efforts to combat this disease,resulting in significant improvement of the situation,with 58 new cases(34 were imported cases)and 11 new deaths reported on March 19,2020.However,as of March 19,2020,the COVID-19 pandemic continues to develop in 167 countries/territories outside of China,and 128665 confirmed cases and 5536 deaths have been reported,with 16498 new cases and 817 new deaths occurring in last 24 hours.Therefore,the world should work together to fight against this pandemic.Here,we review the recent advances in COVID-19,including the insights in the virus,the responses of the host cells,the cytokine release syndrome,and the therapeutic approaches to inhibit the virus and alleviate the cytokine storm.By sharing knowledge and deepening our understanding of the virus and the disease pathogenesis,we believe that the community can efficiently develop effective vaccines and drugs,and the mankind will eventually win this battle against this pandemic.展开更多
The ongoing pandemic of coronavirus disease 19(COVID-19)is caused by a newly discoveredβcoronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).How long the adaptive immunity triggered by SARS-C...The ongoing pandemic of coronavirus disease 19(COVID-19)is caused by a newly discoveredβcoronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination.Here we examined,using ELISA,the IgG antibodies in serum specimens collected from 17 COVID-19 patients at 6–7 months after diagnosis and the results were compared to those from cases investigated 2 weeks to 2 months post-infection.All samples were positive for IgGs against the S-and N-proteins of SARS-CoV-2.Notably,14 samples available at 6–7 months post-infection all showed significant neutralizing activities in a pseudovirus assay,with no difference in blocking the cell-entry of the 614D and 614G variants of SARS-CoV-2.Furthermore,in 10 blood samples from cases at 6–7 months post-infection used for memory T-cell tests,we found that interferonγ-producing CD4+and CD8+cells were increased upon SARS-CoV-2 antigen stimulation.Together,these results indicate that durable anti-SARS-CoV-2 immunity is common in convalescent population,and vaccines developed from 614D variant may offer protection from the currently predominant 614D variant of SARS-CoV-2.展开更多
Since December 2019,an atypical pneumonia has occurred in Wuhan,a beautiful city located at the center of China(Fig.1),and the whole country.The origin of the disease remains unclear and the suspected Huanan Seafood W...Since December 2019,an atypical pneumonia has occurred in Wuhan,a beautiful city located at the center of China(Fig.1),and the whole country.The origin of the disease remains unclear and the suspected Huanan Seafood Wholesale Market was closed on January 1,2020.Very rapidly,a novel coronavirus was isolated and named first the 2019 novel coronavirus(2019-nCoV)[1]and subsequently severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)[2],and is suggested to be named as human coronavirus 2019(HCoV-19)[3].Meanwhile,the disease is chronologically called pneumonia of unknown origin,novel coronavirus pneumonia(NCP),and coronavirus disease-2019(COVID-19)(Fig.2).Superspreading events of this virus have also taken place on the Diamond Princess cruise off the coast of Yokohama,Japan[4].The Chinese central[5]and local governments[6]have been endeavoring unprecedented efforts to constrain the outbreak,and more than 30000 medical professionals especially doctors and nurses outside Wuhan have been joining the local ones to handle this emergency.展开更多
The outbreak of a novel coronavirus disease(COVID-19,caused by the 2019-nCoV infection)in December 2019 is one of the most severe public health emergencies since the founding of People’s Republic of China in 1949.Hea...The outbreak of a novel coronavirus disease(COVID-19,caused by the 2019-nCoV infection)in December 2019 is one of the most severe public health emergencies since the founding of People’s Republic of China in 1949.Healthcare personnel(HCP)nationwide are facing heavy workloads and high risk of infection,especially those who care for patients in Hubei Province.Sadly,as of February 20,2020,over two thousand COVID-19 cases are confirmed among HCP from 476 hospitals nationwide,with nearly 90%of them from Hubei Province.Based on literature search and interviews with some HCP working at Wuhan,capital city of Hubei,we have summarized some of the effective measures taken to reduce infection among HCP,and also made suggestions for improving occupational safety during an infectious disease outbreak.The experience and lessons learned should be a valuable asset for international health community to contain the ongoing COVID-19 epidemic around the world.展开更多
The current standard of care in hematological malignancies has brought considerable clinical benefits to patients.However,important bottlenecks still limit optimal achievements following a current medical practice.The...The current standard of care in hematological malignancies has brought considerable clinical benefits to patients.However,important bottlenecks still limit optimal achievements following a current medical practice.The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders.Consequently,new treatment strategies are necessary to improve clinical outcomes.Chimeric antigen receptor T-cell(CAR T)immunotherapy opens a new path for targeted therapy of hematological malignancies.In this review,through a representative case study,we summarize the current experience of CAR T-cell therapy,the management of common side effects,the causative mechanisms of therapy resistance,and new strategies to improve the efficacy of CAR T-cell therapy.展开更多
OriginalTranslation t(8;21)(q22;q22)acute myeloid leukemia(AML)is a highly heterogeneous hematological malignancy with a high relapse rate in China.Two leukemic myeloblast populations(CD34^(+)CD117^(dim) and CD34^(+)C...OriginalTranslation t(8;21)(q22;q22)acute myeloid leukemia(AML)is a highly heterogeneous hematological malignancy with a high relapse rate in China.Two leukemic myeloblast populations(CD34^(+)CD117^(dim) and CD34^(+)CD117^(bri))were previously identified in t(8;21)AML,and CD34^(+)CD117^(dim) cell proportion was determined as an independent factor for this disease outcome.Here,we examined the impact of CD34^(+)CD117^(dim)/CD34^(+)CD117^(bri) myeloblast-associated gene expression on t(8;21)AML clinical prognosis.In this study,85 patients with t(8;21)AML were enrolled.The mRNA expression levels of CD34^(+)CD117^(dim)-associated genes(LGALS1,EMP3,and CRIP1)and CD34^(+)CD117^(bri)-associated genes(TRH,PLAC8,and IGLL1)were measured using quantitative reverse transcription PCR.Associations between gene expression and clinical outcomes were determined using Cox regression models.Results showed that patients with high LGALS1,EMP3,or CRIP1 expression had significantly inferior overall survival(OS),whereas those with high TRH or PLAC8 expression showed relatively favorable prognosis.Univariate analysis revealed that CD19,CD34^(+)CD117^(dim) proportion,KIT mutation,minimal residual disease(MRD),and expression levels of LGALS1,EMP3,CRIP1,TRH and PLAC8 were associated with OS.Multivariate analysis indicated that KIT mutation,MRD and CRIP1 and TRH expression levels were independent prognostic variables for OS.Identifying the clinical relevance of CD34^(+)CD117^(dim)/CD34^(+)CD117^(bri) myeloblast-associated gene expression may provide new clinically prognostic markers for t(8;21)AML.展开更多
We evaluated the outcomes of chronic myeloid leukemia(CML)patients receiving imatinib treatment in chronic(CP),accelerated(AP),and blast crisis(BP)phases.The single-institution treatment experiences of Chinese patient...We evaluated the outcomes of chronic myeloid leukemia(CML)patients receiving imatinib treatment in chronic(CP),accelerated(AP),and blast crisis(BP)phases.The single-institution treatment experiences of Chinese patients with CML were presented.A total of 275 CML patients(CP,210;AP,24;and BP,41)who received imatinib between February 2001 and April 2008 were enrolled in this study.We evaluated the treatment responses(hematologic,cytogenetic,and molecular),overall survival(OS),event-free survival(EFS),and prognostic factors of outcome.At the cut-off point,the complete cytogenetic response(CCyR)and complete molecular response rates of patients in the CP were 84.7% and 61.9%,respectively,which were significantly higher than those of patients in the AP(50% and 29.1%,respectively,both P<0.001)and BP(24.3% and 9.7%,respectively,both P<0.001).The estimated five-year OS and five-year EFS rates were 93.2% and 86.4% for CP patients,as well as 64.5% and 50.9% for AP patients,which were significantly higher than those for BP patients(P<0.001).In CP patients,univariate analysis revealed that early treatment with imatinib,achieving CCyR within 12 months,additional cytogenetic abnormalities,and kinase domain mutations were associated with the treatment outcome.More patients are needed to carry out multivariate analysis.展开更多
Pathogenic microbes can induce cellular dysfunction,immune response,and cause infectious disease and other diseases including cancers.However,the cellular distributions of pathogens and their impact on host cells rema...Pathogenic microbes can induce cellular dysfunction,immune response,and cause infectious disease and other diseases including cancers.However,the cellular distributions of pathogens and their impact on host cells remain rarely explored due to the limited methods.Taking advantage of single-cell RNA-sequencing(scRNA-seq)analysis,we can assess the transcriptomic features at the single-cell level.Still,the tools used to interpret pathogens(such as viruses,bacteria,and fungi)at the single-cell level remain to be explored.Here,we introduced PathogenTrack,a python-based computational pipeline that uses unmapped scRNA-seq data to identify intracellular pathogens at the single-cell level.In addition,we established an R package named Yeskit to import,integrate,analyze,and interpret pathogen abundance and transcriptomic features in host cells.Robustness of these tools has been tested on various real and simulated scRNA-seq datasets.PathogenTrack is competitive to the state-of-the-art tools such as Viral-Track,and the first tools for identifying bacteria at the single-cell level.Using the raw data of bronchoalveolar lavage fluid samples(BALF)from COVID-19 patients in the SRA database,we found the SARS-CoV-2 virus exists in multiple cell types including epithelial cells and macrophages.SARS-CoV-2-positive neutrophils showed increased expression of genes related to type I interferon pathway and antigen presenting module.Additionally,we observed the Haemophilus parahaemolyticus in some macrophage and epithelial cells,indicating a co-infection of the bacterium in some severe cases of COVID-19.The PathogenTrack pipeline and the Yeskit package are publicly available at GitHub.展开更多
Emerging evidence indicates that the gut microbiome contributes to the host immune response to infectious diseases.Here,to explore the role of the gut microbiome in the host immune responses in COVID-19,we conducted s...Emerging evidence indicates that the gut microbiome contributes to the host immune response to infectious diseases.Here,to explore the role of the gut microbiome in the host immune responses in COVID-19,we conducted shotgun metagenomic sequencing and immune profiling of 14 severe/critical and 24 mild/moderate COVID-19 cases as well as 31 healthy control samples.We found that the diversity of the gut microbiome was reduced in severe/critical COVID-19 cases compared to mild/moderate ones.We identified the abundance of some gut microbes altered post-SARS-CoV-2 infection and related to disease severity,such as Enterococcus faecium,Coprococcus comes,Roseburia intestinalis,Akkermansia ntuciniphila,Bacteroides cellulosilyticus and Blautia obeum.We further analyzed the correlation between the abundance of gut microbes and host responses,and obtained a correlation map between clinical features of COVID-19 and 16 severity-related gut microbe,including Coprococcus comes that was positively correlated with CD3^(+)/CD4^(+)/CD8^(+)lymphocyte counts.In addition,an integrative analysis of gut microbiome and the transcriptome of peripheral blood mononuclear cells(PBMCs)showed that genes related to viral transcription and apoptosis were up-regulated in Coprococcus comes low samples.Moreover,a number of metabolic pathways in gut microbes were also found to be differentially enriched in severe/critical or mild/moderate COVID-19 cases,including the superpathways of polyamine biosynthesis II and sulfur oxidation that were suppressed in severe/critical COVID-19.Together,our study highlighted a potential regulatory role of severity related gut microbes in the immune response of host.展开更多
Background:Heterogeneity of leukemia-initiating cells(LICs)is a major obstacle in acute myeloid leukemia(AML)therapy.Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathoge...Background:Heterogeneity of leukemia-initiating cells(LICs)is a major obstacle in acute myeloid leukemia(AML)therapy.Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathogenicity in the same individual is a common feature in AML.However,the functional heterogeneity including the drug response of coexistent LICs remains unclear.Therefore,this study aimed to clarify the intra-heterogeneity in LICs that can help predict leukemia behavior and develop more effective treatments.Methods:Spleen cells from the primary Setd2^(-/-)-AML mouse were transplanted into C57BL/6 recipient mice to generate a transplantable model.Flow cytometry was used to analyze the immunophenotype of the leukemic mice.Whole-genome sequencing was conducted to detect secondary hits responsible for leukemia transformation.A serial transplantation assay was used to determine the self-renewal potential of Setd2^(-/-)-AML cells.A limiting-dilution assay was performed to identify the LIC frequency in different subsets of leukemia cells.Bulk and single-cell RNA sequencing were performed to analyze the transcriptional heterogeneity of LICs.Small molecular inhibitor screening and in vivo drug treatment were employed to clarify the difference in drug response between the different subsets of LICs.Results:In this study,we observed an aged Setd2^(-/-)mouse developing AML with co-mutation of Nras^(G12S) and Braf^(K520E).Further investigation identified two types of LICs residing in the c-Kit^(+)B220^(+)Mac-1^(-)and c-Kit^(+)B220^(+)Mac-1^(+)subsets,respectively.In vivo transplantation assay disclosed the heterogeneity in differentiation between the coexistent LICs.Besides,an intrinsic doxorubicinresistant transcriptional signature was uncovered in c-Kit^(+)B220^(+)Mac-1^(+)cells.Indeed,doxorubicin plus cytarabine(DA),the standard chemotherapeutic regimen used in AML treatment,could specifically kill c-Kit^(+)B220^(+)Mac-1^(−)cells,but it hardly affected c-Kit^(+)B220^(+)Mac-1^(+)cells.Transcriptome analysis unveiled a higher activation of RAS downstream signaling pathways in c-Kit^(+)B220^(+)Mac-1^(+)cells than in c-Kit^(+)B220^(+)Mac-1^(-)cells.Combined treatmentwithDAand RAS pathway inhibitors killed both c-Kit^(+)B220^(+)Mac-1^(−)and c-Kit^(+)B220^(+)Mac-1^(+)cells and attenuated disease progression.Conclusions:This study identified two cell subsets enriched for LICs inmurine Setd2^(-/-)-AML and disclosed the transcriptional and functional heterogeneity of LICs,revealing that the coexistence of different types of LICs in thismodel brings about diverse drug response.展开更多
The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine research.Though an altered microenvironme...The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine research.Though an altered microenvironment is a general cancer hallmark,how APL blasts shape their plasma composition is poorly understood.Here,we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters,proteomes,and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy.Our study revealed the two prominent features of the APL plasma,suggesting a possible involvement of APL blasts in modulating plasma composition.One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts,and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA.Furthermore,results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage,which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins.Overall,our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.82100158,81890994,81770143,81970130,and 81861148030)Double First-Class Project(No.WF510162602)from the Ministry of Education+8 种基金State Key Laboratory of Medical Genomics,Overseas Expertise Introduction Project for Discipline Innovation(111 Project,No.B17029)National Key R&D Program of China(Nos.2019YFA0905902 and 2018YFA0107802)Natural Science Foundation of Shanghai(Nos.20JC1410600,21ZR1480900,and 21YF1427900)Shanghai Clinical Research Center for Hematologic Disease(No.19MC1910700)Shanghai Major Project for Clinical Medicine(No.2017ZZ01002)Shanghai Shenkang Hospital Development Center(No.SHDC2020CR5002)Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01)Shanghai Jiao Tong University(No.YG2021QN19)Shanghai Guangci Translational Medical Research Development Foundation.
文摘With the recent ongoing autumn/winter 2022 COVID-19 wave and the adjustment of public health control measures,there have been widespread SARS-CoV-2 infections in Chinese mainland.Here we have analyzed 369 viral genomes from recently diagnosed COVID-19 patients in Shanghai,identifying a large number of sublineages of the SARS-CoV-2 Omicron family.Phylogenetic analysis,coupled with contact history tracing,revealed simultaneous community transmission of two Omicron sublineages dominating the infections in some areas of China(BA.5.2 mainly in Guangzhou and Shanghai,and BF.7 mainly in Beijing)and two highly infectious sublineages recently imported from abroad(XBB and BQ.1).Publicly available data from August 31 to November 29,2022 indicated an overall severe/critical case rate of 0.035%nationwide,while analysis of 5706 symptomatic patients treated at the Shanghai Public Health Center between September 1 and December 26,2022 showed that 20 cases(0.35%)without comorbidities progressed into severe/critical conditions and 153 cases(2.68%)with COVID-19-exacerbated comorbidities progressed into severe/critical conditions.These observations shall alert healthcare providers to place more resources for the treatment of severe/critical cases.Furthermore,mathematical modeling predicts this autumn/winter wave might pass through major cities in China by the end of the year,whereas some middle and western provinces and rural areas would be hit by the upcoming infection wave in mid-to-late January 2023,and the duration and magnitude of upcoming outbreak could be dramatically enhanced by the extensive travels during the Spring Festival(January 21,2023).Altogether,these preliminary data highlight the needs to allocate resources to early diagnosis and effective treatment of severe cases and the protection of vulnerable population,especially in the rural areas,to ensure the country’s smooth exit from the ongoing pandemic and accelerate socio-economic recovery.
基金support from the National Natural Science Foundation of China(Nos.82100158 and 81861148030)the Natural Science Foundation of Shanghai(Nos.21ZR1480900 and 21YF1427900)+4 种基金Shanghai Clinical Research Center for Hematologic Disease(No.119MC1910700)ShanghaiMajor Project for Clinical Medicine(No.2017ZZ01002)Shanghai Shenkang Hospital Development Center(No.SHDC2020CR5002)Innovative Research Team of High-level Local Universities in Shanghai,and Shanghai Collaborative Innovation Program on Regenerative Medicineand StemCell Research(No.2019CXJQ01)support from the ASTRA computing platform in the National Research Center for Translational Medicine(Shanghai)and the Pi computing platform in the Center for High-Performance Computing at Shanghai Jiao Tong University.
文摘The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic.Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earlier infection histories during a SARS-CoV-2 outbreak in Shanghai in spring 2022.Compared to an earlier patient cohort infected by SARS-CoV-2 prototype strains in 2020,BA.2.2 infection led to distinct fluctuations of pathophysiological markers in the peripheral blood.In particular,severe/critical cases of COVID19 post BA.2.2 infection were associated with less pro-inflammatory macrophage activation and stronger interferon alpha response in the bronchoalveolar microenvironment.Importantly,the abnormal biomarkers were significantly subdued in individuals who had been immunized by 2 or 3 doses of SARS-CoV-2 prototypeinactivated vaccines,supporting the estimation of an overall 96.02% of protection rate against severe/critical disease in the 4854 cases in our BA.2.2 patient cohort with traceable vaccination records.Furthermore,even though age was a critical risk factor of the severity of COVID-19 post BA.2.2 infection,vaccination-elicited protection against severe/critical COVID-19 reached 90.15% in patients aged≥60 years old.Together,our study delineates the pathophysiological features of Omicron BA.2.2 sublineages and demonstrates significant protection conferred by prior prototype-based inactivated vaccines.
基金supported by the National Key Research and Development Plan of China(No.2018YFA0107802 to Xiaojian Sun,Nos.2018YFA0107200 and 2018YFA0800203 to Lan Wang)the General Program of the National Natural Science Foundation of China(Nos.81470316 and 81670094 to Xiaojian Sun,No.81972339 to Zhe Bao Wu,Nos.81570122 and 81770205 to Jinyan Huang,Nos.81670122 and 81970150 to Lan Wang)+5 种基金the National Research Center for Translational Medicine(Shanghai)grant(No.NRCTM(SH)-2019-05 to Zhe Bao Wu)the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant(No.20152506 to Xiaojian Sun)Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01 to Saijuan Chen and Xiaojian Sun)Innovative Research Team of High-level Local Universities in Shanghai(to Weili Zhao and Xiaojian Sun)the Samuel Waxman Cancer Research Foundationthe Shanghai Guangci Translational Medical Research Development Foundation.
文摘The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In this study,based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins,we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1.This gene,hereby named LY6A,reversely overlaps with a lncRNA gene in the majority of exonic sequences.We found that LY6A is aberrantly expressed in pituitary tumors,but not in normal pituitary tissues,and may contribute to tumorigenesis.Similar to mouse Ly-6A/Sca-1,human LY6A is also upregulated by interferon,suggesting a conserved transcriptional regulatory mechanism between humans and mice.We cloned the full-length LY6A cDNA,whose encoded protein sequence,domain architecture,and exon‒intron structures are all well conserved with mouse Ly-6A/Sca-1.Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane.Collectively,these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.
文摘“The rolling Yangtze River flows eastward,washingaway the heroes in its waves.”These words were written by a poet,Shen Yang,500years ago in his poem Immortal by the River.“Countlessevents of the past and present are all turned into laughterand conversation of the white-haired fishermen andwoodcutters.”
基金supported by the Union for China Lymphoma Investigators,and funded by the Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine(DLY201601)the National Key R&D Program of China(2022YFC 2502600)+3 种基金the National Natural Science Foundation of China(82130004,81830007,82070204,and 81670176)Chang Jiang Scholars Program,Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support(20152206 and 20152208)the Clinical Research Plan of Shanghai Hospital Development Center(SHDC2020CR1032B)the Collaborative Innovation Center of Systems Biomedicine,and the Samuel Waxman Cancer Research Foundation.
文摘Methotrexate,etoposide,dexamethasone,and pegaspargase(MESA)with sandwiched radiotherapy is known to be effective for early-stage extranodal natural killer/T-cell lymphoma,nasal type(NKTCL).We explored the efficacy and safety of reduced-intensity,non-intravenous etoposide,dexamethasone,and pegaspargase(ESA)with sandwiched radiotherapy.This multicenter,randomized,phase III trial enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTCL from 27 centers in China.Patients were randomly assigned(1:1)to receive ESA(pegaspargase 2,500 IU/m^(2)intramuscularly on day 1,etoposide 200 mg orally,and dexamethasone 40 mg orally on days 2–4)or MESA(methotrexate 1 g/m^(2)intravenously on day 1,etoposide 200 mg orally,and dexamethasone 40 mg orally on days 2–4,and pegaspargase 2,500 IU/m^(2)intramuscularly on day 5)regimen(four cycles),combined with sandwiched radiotherapy.
基金This work was supported by the National Natural Science Foundation of China(Nos.82070147,81570122,and 81770205)the National Key Research and Development Program(No.2016YFC0902800)+2 种基金the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(No.20161303)the Innovation Foundation for Doctoral Students of Shanghai Jiao Tong University School of Medicine(Research Grant BXJ201815)the Center for HPC at Shanghai Jiao Tong University.The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.
文摘B-cell precursor acute lymphoblastic leukemia(BCP-ALL)is characterized by genetic alterations with high heterogeneity.Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology.Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes,such as DUX4 rearrangements,MEF2D rearrangements,ZNF384/ZNF362 rearrangements,NUTM1 rearrangements,BCL2/MYC and/or BCL6 rearrangements,ETV6-RUNX1-like gene expression,PAX5alt(diverse PAX5 alterations,including rearrangements,intragenic amplifications,or mutations),and hotspot mutations PAX5(p.Pro80Arg)with biallelic PAX5 alterations,IKZF1(p.Asn159Tyr),and ZEB2(p.His1038Arg).These molecular subtypes could be classified by gene expression patterns with RNA-seq technology.Refined molecular classification greatly improved the treatment strategy.Multiagent therapy regimens,including target inhibitors(e.g.,imatinib),immunomodulators,monoclonal antibodies,and chimeric antigen receptor T-cell(CAR-T)therapy,are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management.We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.
基金This work was supported by the Key Project of the National Natural Science Foundation of China(No.81830093)the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2019-I2M-1-003)+1 种基金Double First-Class Project(No.WF510162602)State Key Laboratory of Medical Genomics of Shanghai Jiao Tong University,Overseas Expertise Introduction Project for Discipline Innovation(111 Project)(No.B17029).
文摘Since the outbreak of the COVID-19 pandemic in early December 2019,81174 confirmed cases and 3242 deaths have been reported in China as of March 19,2020.The Chinese people and government have contributed huge efforts to combat this disease,resulting in significant improvement of the situation,with 58 new cases(34 were imported cases)and 11 new deaths reported on March 19,2020.However,as of March 19,2020,the COVID-19 pandemic continues to develop in 167 countries/territories outside of China,and 128665 confirmed cases and 5536 deaths have been reported,with 16498 new cases and 817 new deaths occurring in last 24 hours.Therefore,the world should work together to fight against this pandemic.Here,we review the recent advances in COVID-19,including the insights in the virus,the responses of the host cells,the cytokine release syndrome,and the therapeutic approaches to inhibit the virus and alleviate the cytokine storm.By sharing knowledge and deepening our understanding of the virus and the disease pathogenesis,we believe that the community can efficiently develop effective vaccines and drugs,and the mankind will eventually win this battle against this pandemic.
基金This work was supported by grant from Double First-Class Project(No.WF510162602)from the Ministry of Education,State Key Laboratory of Medical Genomics,Overseas Expertise Introduction Project for Discipline Innovation(111 Project,No.Bl7029)+1 种基金National Key R&D Program of China(No.2019YFA0905902)the Shanghai Guangci Translational Medical Research Development Foundation。
文摘The ongoing pandemic of coronavirus disease 19(COVID-19)is caused by a newly discoveredβcoronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).How long the adaptive immunity triggered by SARS-CoV-2 can last is of critical clinical relevance in assessing the probability of second infection and efficacy of vaccination.Here we examined,using ELISA,the IgG antibodies in serum specimens collected from 17 COVID-19 patients at 6–7 months after diagnosis and the results were compared to those from cases investigated 2 weeks to 2 months post-infection.All samples were positive for IgGs against the S-and N-proteins of SARS-CoV-2.Notably,14 samples available at 6–7 months post-infection all showed significant neutralizing activities in a pseudovirus assay,with no difference in blocking the cell-entry of the 614D and 614G variants of SARS-CoV-2.Furthermore,in 10 blood samples from cases at 6–7 months post-infection used for memory T-cell tests,we found that interferonγ-producing CD4+and CD8+cells were increased upon SARS-CoV-2 antigen stimulation.Together,these results indicate that durable anti-SARS-CoV-2 immunity is common in convalescent population,and vaccines developed from 614D variant may offer protection from the currently predominant 614D variant of SARS-CoV-2.
文摘Since December 2019,an atypical pneumonia has occurred in Wuhan,a beautiful city located at the center of China(Fig.1),and the whole country.The origin of the disease remains unclear and the suspected Huanan Seafood Wholesale Market was closed on January 1,2020.Very rapidly,a novel coronavirus was isolated and named first the 2019 novel coronavirus(2019-nCoV)[1]and subsequently severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)[2],and is suggested to be named as human coronavirus 2019(HCoV-19)[3].Meanwhile,the disease is chronologically called pneumonia of unknown origin,novel coronavirus pneumonia(NCP),and coronavirus disease-2019(COVID-19)(Fig.2).Superspreading events of this virus have also taken place on the Diamond Princess cruise off the coast of Yokohama,Japan[4].The Chinese central[5]and local governments[6]have been endeavoring unprecedented efforts to constrain the outbreak,and more than 30000 medical professionals especially doctors and nurses outside Wuhan have been joining the local ones to handle this emergency.
文摘The outbreak of a novel coronavirus disease(COVID-19,caused by the 2019-nCoV infection)in December 2019 is one of the most severe public health emergencies since the founding of People’s Republic of China in 1949.Healthcare personnel(HCP)nationwide are facing heavy workloads and high risk of infection,especially those who care for patients in Hubei Province.Sadly,as of February 20,2020,over two thousand COVID-19 cases are confirmed among HCP from 476 hospitals nationwide,with nearly 90%of them from Hubei Province.Based on literature search and interviews with some HCP working at Wuhan,capital city of Hubei,we have summarized some of the effective measures taken to reduce infection among HCP,and also made suggestions for improving occupational safety during an infectious disease outbreak.The experience and lessons learned should be a valuable asset for international health community to contain the ongoing COVID-19 epidemic around the world.
基金funded by the State Key Laboratory of Medical Genomics,the Double First-Class Project(No.WF510162602)from the Ministry of Educationthe Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01)+5 种基金the Overseas Expertise Introduction Project for Discipline Innovation(111 ProjectNo.B17029)the National Natural Science Foundation of China(Nos.82070227,81861148030,81670147,and 81970189)Clinical Research Plan of SHDC(No.SHDC2020CR2066B)the Shanghai Major Project for Clinical Medicine(No.2017ZZ01002)the Innovative Research Team of High-level Local Universities in Shanghai,National Science and Technology Major Project(No.2019ZX09301139).
文摘The current standard of care in hematological malignancies has brought considerable clinical benefits to patients.However,important bottlenecks still limit optimal achievements following a current medical practice.The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders.Consequently,new treatment strategies are necessary to improve clinical outcomes.Chimeric antigen receptor T-cell(CAR T)immunotherapy opens a new path for targeted therapy of hematological malignancies.In this review,through a representative case study,we summarize the current experience of CAR T-cell therapy,the management of common side effects,the causative mechanisms of therapy resistance,and new strategies to improve the efficacy of CAR T-cell therapy.
基金This study was supported by the National Natural Science Foundation of China(No.81800147)Shanghai Sailing Program(No.18YF1413700)+2 种基金the National Key Research and Development Plan of China(No.2018YFA0107800)the National Natural Science Foundation of China(No.81890994)the National Key Research and Development Plan of China(No.2017YFA0506200)。
文摘OriginalTranslation t(8;21)(q22;q22)acute myeloid leukemia(AML)is a highly heterogeneous hematological malignancy with a high relapse rate in China.Two leukemic myeloblast populations(CD34^(+)CD117^(dim) and CD34^(+)CD117^(bri))were previously identified in t(8;21)AML,and CD34^(+)CD117^(dim) cell proportion was determined as an independent factor for this disease outcome.Here,we examined the impact of CD34^(+)CD117^(dim)/CD34^(+)CD117^(bri) myeloblast-associated gene expression on t(8;21)AML clinical prognosis.In this study,85 patients with t(8;21)AML were enrolled.The mRNA expression levels of CD34^(+)CD117^(dim)-associated genes(LGALS1,EMP3,and CRIP1)and CD34^(+)CD117^(bri)-associated genes(TRH,PLAC8,and IGLL1)were measured using quantitative reverse transcription PCR.Associations between gene expression and clinical outcomes were determined using Cox regression models.Results showed that patients with high LGALS1,EMP3,or CRIP1 expression had significantly inferior overall survival(OS),whereas those with high TRH or PLAC8 expression showed relatively favorable prognosis.Univariate analysis revealed that CD19,CD34^(+)CD117^(dim) proportion,KIT mutation,minimal residual disease(MRD),and expression levels of LGALS1,EMP3,CRIP1,TRH and PLAC8 were associated with OS.Multivariate analysis indicated that KIT mutation,MRD and CRIP1 and TRH expression levels were independent prognostic variables for OS.Identifying the clinical relevance of CD34^(+)CD117^(dim)/CD34^(+)CD117^(bri) myeloblast-associated gene expression may provide new clinically prognostic markers for t(8;21)AML.
文摘We evaluated the outcomes of chronic myeloid leukemia(CML)patients receiving imatinib treatment in chronic(CP),accelerated(AP),and blast crisis(BP)phases.The single-institution treatment experiences of Chinese patients with CML were presented.A total of 275 CML patients(CP,210;AP,24;and BP,41)who received imatinib between February 2001 and April 2008 were enrolled in this study.We evaluated the treatment responses(hematologic,cytogenetic,and molecular),overall survival(OS),event-free survival(EFS),and prognostic factors of outcome.At the cut-off point,the complete cytogenetic response(CCyR)and complete molecular response rates of patients in the CP were 84.7% and 61.9%,respectively,which were significantly higher than those of patients in the AP(50% and 29.1%,respectively,both P<0.001)and BP(24.3% and 9.7%,respectively,both P<0.001).The estimated five-year OS and five-year EFS rates were 93.2% and 86.4% for CP patients,as well as 64.5% and 50.9% for AP patients,which were significantly higher than those for BP patients(P<0.001).In CP patients,univariate analysis revealed that early treatment with imatinib,achieving CCyR within 12 months,additional cytogenetic abnormalities,and kinase domain mutations were associated with the treatment outcome.More patients are needed to carry out multivariate analysis.
基金This work was supported by grants from National Natural Science Foundation of China(Nos.8210010124 and 81890994)Double First-Class Project(No.WF510162602)+3 种基金National Key R&D Program of China(No.2019YFA0905902)Natural Science Foundation of Shanghai(Nos.21ZR1480900 and 21YF1427900)Shanghai Jiao Tong University(No.YG2021-QN19)the Shanghai Guangci Translational Medical Research Development Foundation.
文摘Pathogenic microbes can induce cellular dysfunction,immune response,and cause infectious disease and other diseases including cancers.However,the cellular distributions of pathogens and their impact on host cells remain rarely explored due to the limited methods.Taking advantage of single-cell RNA-sequencing(scRNA-seq)analysis,we can assess the transcriptomic features at the single-cell level.Still,the tools used to interpret pathogens(such as viruses,bacteria,and fungi)at the single-cell level remain to be explored.Here,we introduced PathogenTrack,a python-based computational pipeline that uses unmapped scRNA-seq data to identify intracellular pathogens at the single-cell level.In addition,we established an R package named Yeskit to import,integrate,analyze,and interpret pathogen abundance and transcriptomic features in host cells.Robustness of these tools has been tested on various real and simulated scRNA-seq datasets.PathogenTrack is competitive to the state-of-the-art tools such as Viral-Track,and the first tools for identifying bacteria at the single-cell level.Using the raw data of bronchoalveolar lavage fluid samples(BALF)from COVID-19 patients in the SRA database,we found the SARS-CoV-2 virus exists in multiple cell types including epithelial cells and macrophages.SARS-CoV-2-positive neutrophils showed increased expression of genes related to type I interferon pathway and antigen presenting module.Additionally,we observed the Haemophilus parahaemolyticus in some macrophage and epithelial cells,indicating a co-infection of the bacterium in some severe cases of COVID-19.The PathogenTrack pipeline and the Yeskit package are publicly available at GitHub.
基金This work was supported by the National Basic Research Program of China (No. 2013CB966800), Ministry of Health (No.201202003), the Mega-projects of Scientific Research for the 12th Five-Year Plan (No. 2013ZX09303302), the State Key Laboratories Project ofExcellence (No. 81123005), the National Natural Science Foundation of China (Nos. 81222004 and 81170506), and the Samuel Waxman Cancer Research Foundation Co-PI Program.
基金This work was supported by grants from National Natural Science Foundation of China(Nos.8210010124,81890994,and 81861148030)Double First-Class Project(No.WF510162602)from the Ministry of Education+7 种基金State Key Laboratory of Medical Genomics,Overseas Expertise Introduction Project for Discipline Innovation(111 Project,No.B17029)National Key R&D Program of China(No.2019YFA0905902)Natural Science Foundation of Shanghai(Nos.21ZR1480900 and 21YF1427900)Shanghai Clinical Research Center for Hematologic Disease(No.19MC1910700)Shanghai Major Project for Clinical Medicine(No.2017ZZ01002)Shanghai Shenkang Hospital Development Center(No.SHDC2020CR5002)Innovative Research Team of High-level Local Universities in Shanghai,Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01)Shanghai Jiao Tong University(No.YG2021QN19),Shanghai Guangci Translational Medical Research Development Foundation.
文摘Emerging evidence indicates that the gut microbiome contributes to the host immune response to infectious diseases.Here,to explore the role of the gut microbiome in the host immune responses in COVID-19,we conducted shotgun metagenomic sequencing and immune profiling of 14 severe/critical and 24 mild/moderate COVID-19 cases as well as 31 healthy control samples.We found that the diversity of the gut microbiome was reduced in severe/critical COVID-19 cases compared to mild/moderate ones.We identified the abundance of some gut microbes altered post-SARS-CoV-2 infection and related to disease severity,such as Enterococcus faecium,Coprococcus comes,Roseburia intestinalis,Akkermansia ntuciniphila,Bacteroides cellulosilyticus and Blautia obeum.We further analyzed the correlation between the abundance of gut microbes and host responses,and obtained a correlation map between clinical features of COVID-19 and 16 severity-related gut microbe,including Coprococcus comes that was positively correlated with CD3^(+)/CD4^(+)/CD8^(+)lymphocyte counts.In addition,an integrative analysis of gut microbiome and the transcriptome of peripheral blood mononuclear cells(PBMCs)showed that genes related to viral transcription and apoptosis were up-regulated in Coprococcus comes low samples.Moreover,a number of metabolic pathways in gut microbes were also found to be differentially enriched in severe/critical or mild/moderate COVID-19 cases,including the superpathways of polyamine biosynthesis II and sulfur oxidation that were suppressed in severe/critical COVID-19.Together,our study highlighted a potential regulatory role of severity related gut microbes in the immune response of host.
基金National Natural Science Foundation of China,Grant/Award Numbers:81670149,81870102Samuel Waxman Cancer Research FoundationFoundation of Key Laboratory of Veterinary Biotechnology,Grant/Award Number:shklab202008。
文摘Background:Heterogeneity of leukemia-initiating cells(LICs)is a major obstacle in acute myeloid leukemia(AML)therapy.Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathogenicity in the same individual is a common feature in AML.However,the functional heterogeneity including the drug response of coexistent LICs remains unclear.Therefore,this study aimed to clarify the intra-heterogeneity in LICs that can help predict leukemia behavior and develop more effective treatments.Methods:Spleen cells from the primary Setd2^(-/-)-AML mouse were transplanted into C57BL/6 recipient mice to generate a transplantable model.Flow cytometry was used to analyze the immunophenotype of the leukemic mice.Whole-genome sequencing was conducted to detect secondary hits responsible for leukemia transformation.A serial transplantation assay was used to determine the self-renewal potential of Setd2^(-/-)-AML cells.A limiting-dilution assay was performed to identify the LIC frequency in different subsets of leukemia cells.Bulk and single-cell RNA sequencing were performed to analyze the transcriptional heterogeneity of LICs.Small molecular inhibitor screening and in vivo drug treatment were employed to clarify the difference in drug response between the different subsets of LICs.Results:In this study,we observed an aged Setd2^(-/-)mouse developing AML with co-mutation of Nras^(G12S) and Braf^(K520E).Further investigation identified two types of LICs residing in the c-Kit^(+)B220^(+)Mac-1^(-)and c-Kit^(+)B220^(+)Mac-1^(+)subsets,respectively.In vivo transplantation assay disclosed the heterogeneity in differentiation between the coexistent LICs.Besides,an intrinsic doxorubicinresistant transcriptional signature was uncovered in c-Kit^(+)B220^(+)Mac-1^(+)cells.Indeed,doxorubicin plus cytarabine(DA),the standard chemotherapeutic regimen used in AML treatment,could specifically kill c-Kit^(+)B220^(+)Mac-1^(−)cells,but it hardly affected c-Kit^(+)B220^(+)Mac-1^(+)cells.Transcriptome analysis unveiled a higher activation of RAS downstream signaling pathways in c-Kit^(+)B220^(+)Mac-1^(+)cells than in c-Kit^(+)B220^(+)Mac-1^(-)cells.Combined treatmentwithDAand RAS pathway inhibitors killed both c-Kit^(+)B220^(+)Mac-1^(−)and c-Kit^(+)B220^(+)Mac-1^(+)cells and attenuated disease progression.Conclusions:This study identified two cell subsets enriched for LICs inmurine Setd2^(-/-)-AML and disclosed the transcriptional and functional heterogeneity of LICs,revealing that the coexistence of different types of LICs in thismodel brings about diverse drug response.
基金supported by the State Key Laboratory of Medical Genomics,the Double First-Class Project(No.WF510162602)from the Ministry of Educationthe Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01)+5 种基金the Overseas Expertise Introduction Project for Discipline Innovation(111 Project,No.B17029)the National Natural Science Foundation of China(Nos.82230006 and 32170663)the Shanghai Clinical Research Center for Hematological disease(No.19MC1910700)the Shanghai Shenkang Hospital Development Center(No.SHDC2020CR5002)the Shanghai Major Project for Clinical Medicine(No.2017ZZ01002)the Innovative Research Team of High-level Local Universities in Shanghai and the Yangfan Program of the Science and Technology Commission of Shanghai Municipality(No.22YF1425500)。
文摘The treatment of PML/RARA+acute promyelocytic leukemia(APL)with all-trans-retinoic acid and arsenic trioxide(ATRA/ATO)has been recognized as a model for translational medicine research.Though an altered microenvironment is a general cancer hallmark,how APL blasts shape their plasma composition is poorly understood.Here,we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters,proteomes,and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy.Our study revealed the two prominent features of the APL plasma,suggesting a possible involvement of APL blasts in modulating plasma composition.One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts,and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA.Furthermore,results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage,which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins.Overall,our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment.