Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found i...Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found in a spectrum of human malignancies,while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis.Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region,resulting in the production of C-terminally truncated mutant ASXL1 proteins.How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogen-esis are unclear.Here,we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes.We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells,and lose the ability to interact with FOXK1/K2.Specific deletion of the mutant allele eliminates the expression of C-termi-nally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1,thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,particularly those involved in glucose metabolism,oxygen sensing,and JAK-STAT3 signaling pathways.In addition to FOXK1/K2,we also identify other DNA-bind-ing transcription regulators including transcription factors(TFs)which interact with wild-type ASXL1,but not C-terminally truncated mutant.Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.展开更多
目的研究骨髓增生异常综合征（MDS）患者中表观遗传调节因子ASXL1基因的突变情况。方法在DNA水平采用聚合酶链反应（PCR）扩增产物片段直接测序分析法检测53例初发MDS患者及20名健康人ASXL1基因第12外显子突变情况，比较ASXL1突变患者...目的研究骨髓增生异常综合征（MDS）患者中表观遗传调节因子ASXL1基因的突变情况。方法在DNA水平采用聚合酶链反应（PCR）扩增产物片段直接测序分析法检测53例初发MDS患者及20名健康人ASXL1基因第12外显子突变情况，比较ASXL1突变患者与野生型患者临床及实验室特征；反转录聚合酶链反应（RT-PCR）扩增产物直接测序分析法检测ASXL1突变在mRNA水平的表达。结果在53例MDS患者中，9例（16.9 %）ASXL1基因突变。共检测出6种突变类型，包括4种移码突变（2例p.Glu635ArgfsX15、3例p.Gly646TrpfsX12、1例p.Ala640GlyfsX14、1例p.Gly790TrpfsX10）和2种无义突变（1例p.Gln1063X和1例p.Gln695X）。所有突变类型均为杂合突变，其中p.Gly790TrpfsX10和p.Gln695X为新发现突变类型。此外还检测到一种单核苷酸多态性（SNP）位点（4例p.Gly652Ser）。20名健康人中检测出pGly652Ser SNP 5名和p.Leu1173Leu SNP 1名。RT-PCR扩增产物片段直接测序可在mRNA水平检测出移码突变（p.Gly646TrpfsX12）。ASXL1突变患者初发时外周血白细胞计数、红细胞计数、血小板计数、血红蛋白、网织红细胞、中性粒细胞绝对值、外周血淋巴细胞比例、T细胞亚群、骨髓原始细胞比例、MDS分型和染色体核型分布与ASXL1野生型患者相比，差异均无统计学意义（均P〉0.05）。结论ASXL1基因在MDS患者中的突变频率较高，且可在mRNA水平检测到ASXL1基因突变。展开更多
BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily prog...BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily progresses to acute myeloid leukemia.The simultaneous incidence of hematologic malignancies and solid tumors is extremely low,and CMML coinciding with lung malignancies is even rarer.Here,we report a case of CMML,with ASXL1 and EZH2 gene mutations,combined with non-small cell lung cancer(lung squamous cell carcinoma).CASE SUMMARY A 63-year-old male,suffering from toothache accompanied by coughing,sputum,and bloody sputum for three months,was given a blood test after experiencing continuous bleeding resulting from a tooth extraction at a local hospital.Based on morphological results,the patient was diagnosed with CMML and bronchoscopy was performed in situ to confirm the diagnosis of squamous cell carcinoma in the lower lobe of the lung.After receiving azacitidine,programmed cell death protein 1,and platinum-based chemotherapy drugs,the patient developed severe myelosuppression and eventually fatal leukocyte stasis and dyspnea.CONCLUSION During the treatment and observation of CMML and be vigilant of the growth of multiple primary malignant tumors.展开更多
目的通过多个肿瘤综合数据库分析ASXL1基因突变对子宫内膜癌(EC)预后的影响及其作用机制。方法全面检索GEPIA、Kaplan-Meier plotter、the Human Protein Atlas、FireBrowse、STRING、UALCAN等数据库,分析其生存曲线、功能富集情况、基...目的通过多个肿瘤综合数据库分析ASXL1基因突变对子宫内膜癌(EC)预后的影响及其作用机制。方法全面检索GEPIA、Kaplan-Meier plotter、the Human Protein Atlas、FireBrowse、STRING、UALCAN等数据库,分析其生存曲线、功能富集情况、基因相关性及信号通路,并进行生物信息学预测。结果 ASXL1基因突变是EC不良预后因素,对总生存期及无复发生存期均产生影响(P<0.001)。相关性分析显示,ASXL1基因突变可能通过表观遗传学,JAK2/STAT3和PI3K/AKT/mTOR信号通路发挥作用;结合功能富集分析,ASXL1突变主要影响PI3K/AKT/mTOR信号通路。结论 ASXL1基因突变是EC患者的不良预后因素,可能通过PI3K/AKT/mTOR信号通路发挥作用,应进一步开展相关生物学研究,并探索PI3K/mTOR等信号通路抑制剂的临床价值。展开更多
基金the National Key R&D Program of China(No.2016YFA0501800 to D.Y.2016YFC1303303 to C.Y.)+5 种基金the NSFC Grant(No.31871431 and No.31821002 to D.Y.81572761,81772655 and 81972646 to Y.T.)the Innovative Research Team of High-Level Local Universities in Shanghai(to D.Y.)the Recruitment Program of Global Experts of China(Y.T.)the Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(V.T.)Shanghai Rising-Star Program(Y.T.).
文摘Additional sex combs-like 1(ASXL1)interacts with BRCA1-associated protein 1(BAP1)deubiquitinase to oppose the polycomb repressive complex 1(PRC1)-mediated histone H2A ubiquitylation.Germline BAP1 mutations are found in a spectrum of human malignancies,while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis.Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region,resulting in the production of C-terminally truncated mutant ASXL1 proteins.How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogen-esis are unclear.Here,we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes.We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells,and lose the ability to interact with FOXK1/K2.Specific deletion of the mutant allele eliminates the expression of C-termi-nally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1,thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes,particularly those involved in glucose metabolism,oxygen sensing,and JAK-STAT3 signaling pathways.In addition to FOXK1/K2,we also identify other DNA-bind-ing transcription regulators including transcription factors(TFs)which interact with wild-type ASXL1,but not C-terminally truncated mutant.Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.
文摘目的研究骨髓增生异常综合征（MDS）患者中表观遗传调节因子ASXL1基因的突变情况。方法在DNA水平采用聚合酶链反应（PCR）扩增产物片段直接测序分析法检测53例初发MDS患者及20名健康人ASXL1基因第12外显子突变情况，比较ASXL1突变患者与野生型患者临床及实验室特征；反转录聚合酶链反应（RT-PCR）扩增产物直接测序分析法检测ASXL1突变在mRNA水平的表达。结果在53例MDS患者中，9例（16.9 %）ASXL1基因突变。共检测出6种突变类型，包括4种移码突变（2例p.Glu635ArgfsX15、3例p.Gly646TrpfsX12、1例p.Ala640GlyfsX14、1例p.Gly790TrpfsX10）和2种无义突变（1例p.Gln1063X和1例p.Gln695X）。所有突变类型均为杂合突变，其中p.Gly790TrpfsX10和p.Gln695X为新发现突变类型。此外还检测到一种单核苷酸多态性（SNP）位点（4例p.Gly652Ser）。20名健康人中检测出pGly652Ser SNP 5名和p.Leu1173Leu SNP 1名。RT-PCR扩增产物片段直接测序可在mRNA水平检测出移码突变（p.Gly646TrpfsX12）。ASXL1突变患者初发时外周血白细胞计数、红细胞计数、血小板计数、血红蛋白、网织红细胞、中性粒细胞绝对值、外周血淋巴细胞比例、T细胞亚群、骨髓原始细胞比例、MDS分型和染色体核型分布与ASXL1野生型患者相比，差异均无统计学意义（均P〉0.05）。结论ASXL1基因在MDS患者中的突变频率较高，且可在mRNA水平检测到ASXL1基因突变。
文摘BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily progresses to acute myeloid leukemia.The simultaneous incidence of hematologic malignancies and solid tumors is extremely low,and CMML coinciding with lung malignancies is even rarer.Here,we report a case of CMML,with ASXL1 and EZH2 gene mutations,combined with non-small cell lung cancer(lung squamous cell carcinoma).CASE SUMMARY A 63-year-old male,suffering from toothache accompanied by coughing,sputum,and bloody sputum for three months,was given a blood test after experiencing continuous bleeding resulting from a tooth extraction at a local hospital.Based on morphological results,the patient was diagnosed with CMML and bronchoscopy was performed in situ to confirm the diagnosis of squamous cell carcinoma in the lower lobe of the lung.After receiving azacitidine,programmed cell death protein 1,and platinum-based chemotherapy drugs,the patient developed severe myelosuppression and eventually fatal leukocyte stasis and dyspnea.CONCLUSION During the treatment and observation of CMML and be vigilant of the growth of multiple primary malignant tumors.
文摘目的通过多个肿瘤综合数据库分析ASXL1基因突变对子宫内膜癌(EC)预后的影响及其作用机制。方法全面检索GEPIA、Kaplan-Meier plotter、the Human Protein Atlas、FireBrowse、STRING、UALCAN等数据库,分析其生存曲线、功能富集情况、基因相关性及信号通路,并进行生物信息学预测。结果 ASXL1基因突变是EC不良预后因素,对总生存期及无复发生存期均产生影响(P<0.001)。相关性分析显示,ASXL1基因突变可能通过表观遗传学,JAK2/STAT3和PI3K/AKT/mTOR信号通路发挥作用;结合功能富集分析,ASXL1突变主要影响PI3K/AKT/mTOR信号通路。结论 ASXL1基因突变是EC患者的不良预后因素,可能通过PI3K/AKT/mTOR信号通路发挥作用,应进一步开展相关生物学研究,并探索PI3K/mTOR等信号通路抑制剂的临床价值。
