应用高通量测序研究儿童血液系统疾病发病机制
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摘要
研究目的
范可尼贫血是一种罕见的遗传性疾病,临床特征是造血功能衰竭,多发性先天畸形,易患恶性肿瘤,患者细胞对DNA交联剂如丝裂霉素C (mitomycin C, MMC)异常敏感。目前已发现15个FA易感基因,均参与维持基因组稳定性功能途径。但1/3患者没有已知FA易感基因变异,而基因敲除小鼠模型并没有明显的FA疾病表型,暗示FA存在新的易感基因以及可能是多基因协同遗传疾病。本实验主要研究范可尼贫血易感基因突变和阐明基因之间的协同作用机制与骨髓造血衰竭发生的关系。
研究方法
采用Illumina HiSeq 2000测序仪,对临床确诊的5例范可尼贫血患者及其父母进行双末端50×全外显子组测序,运用生物信息学手段分析全外显子组点突变、插入、缺失,通过与人类基因组数据库对比分析发现范可尼贫血患者易感基因的突变,通过与父母外显子组序列对比分析发现生长发育过程中新发的基因突变。将高通量测序与传统分子生物学、细胞生物学、动物模型等研究相结合,最终阐明基因之间的协同作用机制与骨髓造血衰竭发生的关系。
实验结果
5例患者经临床表现、外周血彗星实验、MMC实验确诊为范可尼贫血。通过对5例患者全外显子组测序数据分析发现每一例患者在已知的15种范可尼贫血易感基因上都有单基因或多基因突变,突变类型包括单碱基突变(错义突变和无义突变)或插入缺失(移码突变),单碱基突变包括纯合突变、杂合突变、复合杂合突变(一条基因上有多个突变位点),造成蛋白翻译错误或终止。FA易感基因的突变类型及方式各不相同,突变数目不一,与临床表现及严重程度没有相关性,推测易感基因突变引起引起FA的机制是复杂的。如患者WFY在多个FA相关基因发生突变,在FANCA和BRCA2基因上发生了纯合突变,在FANM基因发现符合杂合突变。而患者WSW仅在FANCA基因发现杂合的GG碱基缺失,引起移码突变,通过与父母的外显子数据对比分析发现这个基因突变来自于父亲,但其父亲没有FA临床表现,推测其有未知的基因突变。除FA易感基因外,通过与数据库中基因序列进行比对,并除去由父母中遗传到的SNP,每例患者均发现137-170个新发的基因突变,某些基因突变为多个患者所共有,因此FA患者因DNA交联修复缺陷在后天发育成长过程中不断累积突变。通过KEGG网络调控分析分析结果发现范可尼贫血突变基因不仅涉及各种合成代谢通路、凋亡通路、泛素化通路,而且与多条信号通路相关：钙离子信号通路、WNT信号通路、Notch信号通路、胰岛素信号通路、B细胞受体信号通路、mTOR信号通、MAPK信号通路、VEGF信号通路和T细胞受体信号等。
结论
1)FA易感基因的突变类型及方式各不相同,突变数目不一,与临床表现及严重程度没有相关性。
2)每例患者均发现137-170个新发的基因突变,某些基因突变为多个患者所共有,因此FA患者因DNA交联修复缺陷在后天发育成长过程中不断累积突变。
3)范可尼贫血突变基因影响多种合成代谢通路、凋亡通路、泛素化通路等。
研究目的
鉴定混合谱系白血病中未知的MLL融合基因,研究MLL融合基因和协同致病基因引发白血病的作用机制
研究方法
流过流式细胞仪分选患儿白血病细胞,通过全基因组测序、全转录组测序和表观遗传学修饰研究,系统研究这一对同卵双生儿童的遗传差异及表观遗传影响,从中寻找急性白血病发生中能够和MLL基因染色体易位相互协同的基因组突变。通过PCR测序验证结果的准确性,并在较大样本的急性白血病病人中进行验证。将得到的可能与白血病发病有关基因进行基因敲除、RNA干扰、动物模型构建等功能验证,最终确定其在白血病发生发展中的作用。
结果
患者综合临床表现、骨髓形态学、流式白血病免疫分型和FISH等结果明确诊断为11q23/MLL急性髓系白血病。STR-PCR分析鉴定确定两姐妹为同卵双胞胎。通过SOLID双端全基因组测序和Solexa双端全转录组测序,应用生物信息学分析软件,患病双胞胎姐姐基因组和转录组分析得到MLL-NRIP3和NF1-AARSD1两个融合基因,MLL-NRIP3有3种剪接变异体,而健康妹妹没有分析到融合基因。将姐姐和妹妹的基因组遗传与数据库数据比较及相互比较,发现23个基因突变。按突变类型分,其中1个为无义突变,4个为剪切位点突变,18个为错义突变。按突变方式分,5例为纯合突变,18例为杂合突变。
结论
1)患者综合临床表现、骨髓形态学、流式白血病免疫分型和FISH等结果明确诊断为11q23/MLL急性髓系白血病。
2)患病双胞胎姐姐基因组和转录组分析得到MLL-NRIP3和NF1-AARSD1两个融合基因,MLL-NRIP3有3种剪接变异体,而健康妹妹没有分析到融合基因。将姐姐和妹妹的基因组与数据库及两者相互比较,发现23个基因突变。
研究目的
鉴定家族性x连锁遗传性铁粒幼细胞性贫血致病基因
研究方法
对已知基因进行外显子测序及表达分析,分析是否有突变。若已知基因未检测到突变,则通过对家族中2例患者进行全基因组测序寻找共同的突变基因,将得到的突变基因在未进行测序的2例患者中及明确基因携带的4例携带者中验证。确定突变基因后,进行功能验证。检测3例可能是携带者的基因序列,明确其是否携带致病基因。
结果和结论
已知的致病基因ALAS2外显子区、启动子区及增强子区未发现基因突变,基因表达正常。可能相关的基因ABC7未发现外显子区序列改变。推测该致病基因为未知基因突变。
Objective
Fanconi anemia is a rare genetic disease, characterized by bone marrow failure, congenital malformations, cancer, and hypersensitivity to DNA interstrand cross-linking agents such as mitomycin C. FA has been found 15 susceptibility genes, all involved in maintaining genome stability. But 1/3 patients cannot find Fanc genes mutation, and gene knockout mice have no obvious FA phenotype, suggesting the existence of new FA genes and more susceptibility genes may have cooperative activity. The main objective is to find Fanc gene mutations and new gene mutations, to clarify their synergy effect in causing bone marrow failure.
Methods
The exome of 5 patients of Fanconi anemia and their parents were Sequenced using two-terminal Illumina HiSeq 2000. The sequencing depth was 50×. By bioinformatics analysis, single nucleotide variation insertion、deletion in Fanc gene will be got by comprising with the human genome database, new mutations in other genes with growth will be got by comparising with their parents' exome. Combining high-throughput sequencing and traditional molecular biology, cell biology, animal models and other studies, ultimately clarify the mechanism of the synergy between genes mutation and bone marrow failure.
Results
Five patients were diagnosed by Clinical manifestations, single-cell gel electrophoresis and MMC test. By exome sequencing data analysis all 5 patients showed some of mutations in 15 known Fanconi anemia genes. The gene mutation types included Single nucleotide mutations (missense mutation and a nonsense mutation), or insertion deletion (frameshift mutation). Single nucleotide mutations included homozygous mutations, heterozygous mutations, complex heterozygous mutation (one gene has multiple mutations), resulting in errors or termination of protein translation. Fanc mutations have different types, ways and numbers, and have no correlation with clinical manifestations and severity, suggesting that the mechanism of FA caused by Fanc mutation is complex. For example, patients WFY have 3 genes mutation, the BRCA2 and FANCA had homozygous mutations, while in FANM gene find complex heterozygous mutations. In the mean while patients WSW only have the GG heterozygous deletion in FANCA causing a frameshift mutation, and the mutation was inherited from his father, but his father have no clinical manifestations of FA, suggesting that he may have unknown mutations. In addition to Fanc genes, comparing with the database, and remove the SNP inherited from their parents,137-170 novel mutations were found per patient, Some gene mutations are shared by many patients, so FA patients continue to accumulate mutations due to defects in DNA crosslink repair during postnatal growth. Analysis of the Regulation by KEGG analysis found that Fanconi anemia mutations involve in the network of various synthetic pathways, apoptosis pathway, ubiquitination pathway, the calcium signaling pathway, WNT signaling pathway, Notch signaling pathway, insulin signaling pathway, B cell receptor signaling pathway, mTOR signaling through, MAP K signaling pathway, VEGF signaling pathway and T cell receptor signals.
Conclusion
1) Fanc mutations have different types, ways and numbers, and have no correlation with clinical manifestations and severity, suggesting that the mechanism of FA caused by Fanc mutation is complex.
2) 137-170 novel mutations were found per patient, some gene mutations are shared by many patients, so FA patients continue to accumulate mutations due to defects in DNA crosslink repair during postnatal growth.
3) The Fanconi anemia gene mutations affect a variety of anabolic pathways, apoptosis pathway and ubiquitination pathway.
Objective
Identifying of unknown MLL fusion partner gene, find the Coordination mechanism between the MLL fusion gene and the synergy gene.
Methods
Got pure leukemia cells by Flow sorting. Using whole genome sequencing, whole transcriptome sequencing and epigenetic modification, detect unknown MLL fusion partner gene, identify the genetic differences between monozygotic twins including SNVs, small InDels, structural variations and alternative splicing. The results were PCR amplified and sequenced, and test the mutation in larger sample of patients with acute leukemia. The genes that may participate in leukemia will be verified functionally, and ultimately determine their role in the development of leukemia.
Results
After comprehensive clinical manifestations with bone marrow morphology, flow leukemia immunophenotyping and FISH results, the patients were diagnosed as 11q23/MLL acute myeloid leukemia. STR-PCR analysis identified the two sisters are monozygotic twins. Using Solid pair-ended whole-genome sequencing and Solexa pair-end the whole transcriptome sequencing, the data were analysised by bioinformatics software, the sick sister genome and transcriptome found two fusion genes MLL-NRIP3 and NF1-AARSD1, and MLL-NRIP3 have 3 types of splice variants, while healthy sister did not find any fusion gene. Comparing the twins'genome and transcriptome data with the database,23 mutations were found. Divided by type of mutation, of which one is nonsense mutations,4 are splice sites,18 are missense mutations. Divided by ways of mutation,5 cases are homozygous mutations, and 18 are heterozygous mutations.
Conclusion
1) After comprehensive clinical manifestations with bone marrow morphology, flow leukemia immunophenotyping and FISH results, the patients were diagnosed as 11q23/MLL acute myeloid leukemia.
2) The sick sister genome and transcriptome found two fusion genes MLL-NRIP3 and NF1-AARSD1, and MLL-NRIP3 have 3 types of splice variants, while healthy sister did not find any fusion gene.
3) Comparing the twins'genome and transcriptome data with the database,23 mutations were found.
Objective
Identification of the mutation gene in a family X-linked sideroblastic anemia
Methods
Each ALAS2 exon was PCR amplified and sequenced, analysis whether there are mutations. If a known gene mutation is not detected, then using DNA sequencing to find shared mutation, the mutant gene will be sequenced in other 2 patients and 4 cases of specific gene carriers. Detected the gene sequence in three cases who may be potential earners.
Results and conclusions
To determine the nature of the mutation in the ALAS2 gene causing family XLSA, genomic DNAs were isolated from two affected patients, and each ALAS2 exon was PCR amplified and sequenced. No nucleotide changes were found by sequencing each of the regional, including intron/exon boundaries,1 kb of 5'flanking and the 8th intron sequence. The expression level of ALAS2 gene is normal. No nucleotide changes were found by sequencing each of exon of ABC7 gene.Speculated that the causative gene mutation is unknown.
范可尼贫血是一种罕见的遗传性疾病,临床特征是造血功能衰竭,多发性先天畸形,易患恶性肿瘤,患者细胞对DNA交联剂如丝裂霉素C (mitomycin C, MMC)异常敏感。目前已发现15个FA易感基因,均参与维持基因组稳定性功能途径。但1/3患者没有已知FA易感基因变异,而基因敲除小鼠模型并没有明显的FA疾病表型,暗示FA存在新的易感基因以及可能是多基因协同遗传疾病。本实验主要研究范可尼贫血易感基因突变和阐明基因之间的协同作用机制与骨髓造血衰竭发生的关系。
研究方法
采用Illumina HiSeq 2000测序仪,对临床确诊的5例范可尼贫血患者及其父母进行双末端50×全外显子组测序,运用生物信息学手段分析全外显子组点突变、插入、缺失,通过与人类基因组数据库对比分析发现范可尼贫血患者易感基因的突变,通过与父母外显子组序列对比分析发现生长发育过程中新发的基因突变。将高通量测序与传统分子生物学、细胞生物学、动物模型等研究相结合,最终阐明基因之间的协同作用机制与骨髓造血衰竭发生的关系。
实验结果
5例患者经临床表现、外周血彗星实验、MMC实验确诊为范可尼贫血。通过对5例患者全外显子组测序数据分析发现每一例患者在已知的15种范可尼贫血易感基因上都有单基因或多基因突变,突变类型包括单碱基突变(错义突变和无义突变)或插入缺失(移码突变),单碱基突变包括纯合突变、杂合突变、复合杂合突变(一条基因上有多个突变位点),造成蛋白翻译错误或终止。FA易感基因的突变类型及方式各不相同,突变数目不一,与临床表现及严重程度没有相关性,推测易感基因突变引起引起FA的机制是复杂的。如患者WFY在多个FA相关基因发生突变,在FANCA和BRCA2基因上发生了纯合突变,在FANM基因发现符合杂合突变。而患者WSW仅在FANCA基因发现杂合的GG碱基缺失,引起移码突变,通过与父母的外显子数据对比分析发现这个基因突变来自于父亲,但其父亲没有FA临床表现,推测其有未知的基因突变。除FA易感基因外,通过与数据库中基因序列进行比对,并除去由父母中遗传到的SNP,每例患者均发现137-170个新发的基因突变,某些基因突变为多个患者所共有,因此FA患者因DNA交联修复缺陷在后天发育成长过程中不断累积突变。通过KEGG网络调控分析分析结果发现范可尼贫血突变基因不仅涉及各种合成代谢通路、凋亡通路、泛素化通路,而且与多条信号通路相关：钙离子信号通路、WNT信号通路、Notch信号通路、胰岛素信号通路、B细胞受体信号通路、mTOR信号通、MAPK信号通路、VEGF信号通路和T细胞受体信号等。
结论
1)FA易感基因的突变类型及方式各不相同,突变数目不一,与临床表现及严重程度没有相关性。
2)每例患者均发现137-170个新发的基因突变,某些基因突变为多个患者所共有,因此FA患者因DNA交联修复缺陷在后天发育成长过程中不断累积突变。
3)范可尼贫血突变基因影响多种合成代谢通路、凋亡通路、泛素化通路等。
研究目的
鉴定混合谱系白血病中未知的MLL融合基因,研究MLL融合基因和协同致病基因引发白血病的作用机制
研究方法
流过流式细胞仪分选患儿白血病细胞,通过全基因组测序、全转录组测序和表观遗传学修饰研究,系统研究这一对同卵双生儿童的遗传差异及表观遗传影响,从中寻找急性白血病发生中能够和MLL基因染色体易位相互协同的基因组突变。通过PCR测序验证结果的准确性,并在较大样本的急性白血病病人中进行验证。将得到的可能与白血病发病有关基因进行基因敲除、RNA干扰、动物模型构建等功能验证,最终确定其在白血病发生发展中的作用。
结果
患者综合临床表现、骨髓形态学、流式白血病免疫分型和FISH等结果明确诊断为11q23/MLL急性髓系白血病。STR-PCR分析鉴定确定两姐妹为同卵双胞胎。通过SOLID双端全基因组测序和Solexa双端全转录组测序,应用生物信息学分析软件,患病双胞胎姐姐基因组和转录组分析得到MLL-NRIP3和NF1-AARSD1两个融合基因,MLL-NRIP3有3种剪接变异体,而健康妹妹没有分析到融合基因。将姐姐和妹妹的基因组遗传与数据库数据比较及相互比较,发现23个基因突变。按突变类型分,其中1个为无义突变,4个为剪切位点突变,18个为错义突变。按突变方式分,5例为纯合突变,18例为杂合突变。
结论
1)患者综合临床表现、骨髓形态学、流式白血病免疫分型和FISH等结果明确诊断为11q23/MLL急性髓系白血病。
2)患病双胞胎姐姐基因组和转录组分析得到MLL-NRIP3和NF1-AARSD1两个融合基因,MLL-NRIP3有3种剪接变异体,而健康妹妹没有分析到融合基因。将姐姐和妹妹的基因组与数据库及两者相互比较,发现23个基因突变。
研究目的
鉴定家族性x连锁遗传性铁粒幼细胞性贫血致病基因
研究方法
对已知基因进行外显子测序及表达分析,分析是否有突变。若已知基因未检测到突变,则通过对家族中2例患者进行全基因组测序寻找共同的突变基因,将得到的突变基因在未进行测序的2例患者中及明确基因携带的4例携带者中验证。确定突变基因后,进行功能验证。检测3例可能是携带者的基因序列,明确其是否携带致病基因。
结果和结论
已知的致病基因ALAS2外显子区、启动子区及增强子区未发现基因突变,基因表达正常。可能相关的基因ABC7未发现外显子区序列改变。推测该致病基因为未知基因突变。
Objective
Fanconi anemia is a rare genetic disease, characterized by bone marrow failure, congenital malformations, cancer, and hypersensitivity to DNA interstrand cross-linking agents such as mitomycin C. FA has been found 15 susceptibility genes, all involved in maintaining genome stability. But 1/3 patients cannot find Fanc genes mutation, and gene knockout mice have no obvious FA phenotype, suggesting the existence of new FA genes and more susceptibility genes may have cooperative activity. The main objective is to find Fanc gene mutations and new gene mutations, to clarify their synergy effect in causing bone marrow failure.
Methods
The exome of 5 patients of Fanconi anemia and their parents were Sequenced using two-terminal Illumina HiSeq 2000. The sequencing depth was 50×. By bioinformatics analysis, single nucleotide variation insertion、deletion in Fanc gene will be got by comprising with the human genome database, new mutations in other genes with growth will be got by comparising with their parents' exome. Combining high-throughput sequencing and traditional molecular biology, cell biology, animal models and other studies, ultimately clarify the mechanism of the synergy between genes mutation and bone marrow failure.
Results
Five patients were diagnosed by Clinical manifestations, single-cell gel electrophoresis and MMC test. By exome sequencing data analysis all 5 patients showed some of mutations in 15 known Fanconi anemia genes. The gene mutation types included Single nucleotide mutations (missense mutation and a nonsense mutation), or insertion deletion (frameshift mutation). Single nucleotide mutations included homozygous mutations, heterozygous mutations, complex heterozygous mutation (one gene has multiple mutations), resulting in errors or termination of protein translation. Fanc mutations have different types, ways and numbers, and have no correlation with clinical manifestations and severity, suggesting that the mechanism of FA caused by Fanc mutation is complex. For example, patients WFY have 3 genes mutation, the BRCA2 and FANCA had homozygous mutations, while in FANM gene find complex heterozygous mutations. In the mean while patients WSW only have the GG heterozygous deletion in FANCA causing a frameshift mutation, and the mutation was inherited from his father, but his father have no clinical manifestations of FA, suggesting that he may have unknown mutations. In addition to Fanc genes, comparing with the database, and remove the SNP inherited from their parents,137-170 novel mutations were found per patient, Some gene mutations are shared by many patients, so FA patients continue to accumulate mutations due to defects in DNA crosslink repair during postnatal growth. Analysis of the Regulation by KEGG analysis found that Fanconi anemia mutations involve in the network of various synthetic pathways, apoptosis pathway, ubiquitination pathway, the calcium signaling pathway, WNT signaling pathway, Notch signaling pathway, insulin signaling pathway, B cell receptor signaling pathway, mTOR signaling through, MAP K signaling pathway, VEGF signaling pathway and T cell receptor signals.
Conclusion
1) Fanc mutations have different types, ways and numbers, and have no correlation with clinical manifestations and severity, suggesting that the mechanism of FA caused by Fanc mutation is complex.
2) 137-170 novel mutations were found per patient, some gene mutations are shared by many patients, so FA patients continue to accumulate mutations due to defects in DNA crosslink repair during postnatal growth.
3) The Fanconi anemia gene mutations affect a variety of anabolic pathways, apoptosis pathway and ubiquitination pathway.
Objective
Identifying of unknown MLL fusion partner gene, find the Coordination mechanism between the MLL fusion gene and the synergy gene.
Methods
Got pure leukemia cells by Flow sorting. Using whole genome sequencing, whole transcriptome sequencing and epigenetic modification, detect unknown MLL fusion partner gene, identify the genetic differences between monozygotic twins including SNVs, small InDels, structural variations and alternative splicing. The results were PCR amplified and sequenced, and test the mutation in larger sample of patients with acute leukemia. The genes that may participate in leukemia will be verified functionally, and ultimately determine their role in the development of leukemia.
Results
After comprehensive clinical manifestations with bone marrow morphology, flow leukemia immunophenotyping and FISH results, the patients were diagnosed as 11q23/MLL acute myeloid leukemia. STR-PCR analysis identified the two sisters are monozygotic twins. Using Solid pair-ended whole-genome sequencing and Solexa pair-end the whole transcriptome sequencing, the data were analysised by bioinformatics software, the sick sister genome and transcriptome found two fusion genes MLL-NRIP3 and NF1-AARSD1, and MLL-NRIP3 have 3 types of splice variants, while healthy sister did not find any fusion gene. Comparing the twins'genome and transcriptome data with the database,23 mutations were found. Divided by type of mutation, of which one is nonsense mutations,4 are splice sites,18 are missense mutations. Divided by ways of mutation,5 cases are homozygous mutations, and 18 are heterozygous mutations.
Conclusion
1) After comprehensive clinical manifestations with bone marrow morphology, flow leukemia immunophenotyping and FISH results, the patients were diagnosed as 11q23/MLL acute myeloid leukemia.
2) The sick sister genome and transcriptome found two fusion genes MLL-NRIP3 and NF1-AARSD1, and MLL-NRIP3 have 3 types of splice variants, while healthy sister did not find any fusion gene.
3) Comparing the twins'genome and transcriptome data with the database,23 mutations were found.
Objective
Identification of the mutation gene in a family X-linked sideroblastic anemia
Methods
Each ALAS2 exon was PCR amplified and sequenced, analysis whether there are mutations. If a known gene mutation is not detected, then using DNA sequencing to find shared mutation, the mutant gene will be sequenced in other 2 patients and 4 cases of specific gene carriers. Detected the gene sequence in three cases who may be potential earners.
Results and conclusions
To determine the nature of the mutation in the ALAS2 gene causing family XLSA, genomic DNAs were isolated from two affected patients, and each ALAS2 exon was PCR amplified and sequenced. No nucleotide changes were found by sequencing each of the regional, including intron/exon boundaries,1 kb of 5'flanking and the 8th intron sequence. The expression level of ALAS2 gene is normal. No nucleotide changes were found by sequencing each of exon of ABC7 gene.Speculated that the causative gene mutation is unknown.
引文
[1]Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature.2001;409(6822):860-921.
[2]Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science.2001,291(5507):1304-51.
[3]Kμllo IJ, Cooper LT.Early identification of cardiovascμlar risk using genomics and proteomics. Nat Rev Cardiol.2010 Jun;7(6):309-17
[4]McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits:consensus, uncertainty and challenges. Nat Rev Genet.2008 May;9(5):356-69.
[5]Hudson TJ, Anderson W, Artez A, et al. International network of cancer genome projects.Nature.2010 Apr 15;464(7291):993-8
[6]Nowell PC, Hungerford DA. A minute chromosome in human granμlocytic leukemia. Science 1960;132:1497.
[7]Moran G, Stokes C, Thewes S, Hube B, Coleman DC, Sμllivan D. Comparative genomics using Candida albicans DNA microarrays reveals absence and divergence of virμlence-associated genes in Candida dubliniensis. Microbiology 2004150 (Pt 10): 3363-3382.
[8]Tyybakinoja A, Elonen E, Piippo K, Porkka K, Knuutila S. Oligonucleotide array-CGH reveals cryptic gene copy number alterations in karyotypically normal acute myeloid leukemia. Leukemia 2007;21 (3):571-574.
[9]Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358(18):1909-1918.
[10]Elaine R.Mardis, Li Ding, Timothy J. Ley, et.al DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome Vol 456 6 November 2008 doi:10.1038/nature07485
[11]D'Andrea AD.Susceptibility pathways in Fanconi's anemia and breast cancer.N Engl J Med.2010 May 20;362(20):1909-19.
[12]Zwijnenburg PJ, Meijers-Heijboer H, Boomsma Dl.Identical but not the same:the value of discordant monozygotic twins in genetic research. Am J Med Genet B Neuropsychiatr Genet.2010 Sep;153B(6):1134-49.
[13]Bergmann AK, Campagna DR, McLoughlin EM, et al. Systematic Molecμlar Genetic Analysis of Congenital Sideroblastic Anemia:Evidence for Genetic Heterogeneity and Identification of Novel Mutations. Pediatr Blood Cancer.2010 Feb;54(2):273-8
[14]Chin L, Andersen JN, Futreal PA.Cancer genomics:from discovery science to personalized medicine. Nat Med.2011 Mar;17(3):297-303.
[1]Jacquemont C,Taniguchi T. The fanconi anemia pathway and ubiquitin[J].BMC Biochem,2007,8 Suppl 1:S10.
[2]Callen E, Casado JA, Tischkowitz MD, et al.A common founder mutation in FANCA underlies the world's highest prevalence of fanconi anemia in Gypsy families from Spain [J].Blood 2005,105 (5):1946-1949.
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[6]Giampietro PF, Verlander PC, Maschan A, et al. Fanconi anemia:A model for somatic gene mutation during development. Am J Med Genet 1994,52:36-37
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[8]D'Andrea AD.Susceptibility pathways infanconi's anemia and breast cancer.N Engl J Med.2010 May 20;362(20):1909-19.
[9]StoepkeNat Genet, r C, Hain K, Schuster B,et al.SLX4, a coordinator of structure-specific endonucleases, is mutated in a new fanconi anemia subtype.2011 Feb;43(2):138-41. Epub 2011 Jan 16
[10]Vaz F, Hanenberg H, Schuster B.et al. Mutation of the RAD51C gene in a fanconi anemia-like disorder. Nat Genet.2010 May; 42(5):406-9. Epub 2010 Apr 18
[11]Garcia-Higuera, T. Taniguchi, S. Ganesan, et al. Interaction of the fanconi anemia proteins and BRCA1 in a common pathway, Mol. Cell 7 (2001) 249-262.
[12]A.R. Meetei, J.P. de Winter, A.L. Medhurst,et al. A novel ubiquitin ligase is deficient in fanconi anemia, Nat. Genet.35 (2003)165-170.
[13]X. Wang, P.R. Andreassen, D'Andrea, Functional interaction of monoubiq-uitinated FANCD2 and BRCA2/FANCD1 in chromatin, Mol. Cell. Biol.24 (2004) 5850-5862.
[14]Kalindi Parmara, Alan D'Andreaa, Laura J. Niedernhofer. Mouse models of fanconi anemia. Mutation Research 668 (2009) 133-140.
[15]B. Freie, X. Li, S.L. Ciccone, et al. Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis, Blood 102 (2003) 4146-4152
[16]M.A. Whitney, G. Royle, M.J. Low, et al. Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the fanconi anemia C gene, Blood 88 (1996)49-58
[17]张之南,沈悌.《血液病诊断及疗效标准》[M].北京：科学出版社,2007：24-25
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[19]Raya A, Rodriguez-Piza I, Guenechea G, et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells.Nature.2009;460 (7251):53-9.
[1]Chowdhury T,Brady HJ.Insights from clinical studies into the role of the MLL gene in infant and childhood leukemia.Blood Cells MolDis,2008,40:192-199.
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[4]Meyer C, R Marschalek. LDI-PCR:identification of known and unknown gene fusions of the human MLL gene. Methods Mol Biol.2009;538:71-83.
[5]Marschalek, R. Mechanisms of leukemogenesis by MLL fusion proteins. Br J Haematol.2011 Jan;152(2):141-54
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[8]Krivtsov AV, Feng Z, Lemieux ME,et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell.2008 Nov 4;14(5):355-68.
[9]Steven H Swerdlow, Elias Campo,Nancy Lee Harris,et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues[M]. Lyon,France,Internationl Agency for Research on Cancer.2008:29.
[10]Pallisgaard N, Hokland P, et al.. "Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia." Blood 92(2):574-588.
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[12]Maureen D, Megonigal, Eric F, et al. Panhandle PCR for Cdna:A rapid method for isolation of MLL fusion transcripts involving unknown partner genes.PNAS, 2000,97(17):9597-9602.
[13]Brian V, BalgobindC, Michel Zwaan,et al. NRIP3:a novel translocation partner of MLL detected in a pediatric acute myeloid leukemia with complex chromosome 11 rearrangements. Haematologica,2009; 94(7):1033-1034
[1]Bergmann AK, Campagna DR, McLoughlin EM, et al. Systematic Molecμlar Genetic Analysis of Congenital Sideroblastic Anemia:Evidence for Genetic Heterogeneity and Identification of Novel Mutations. Pediatr Blood Cancer.2010 Feb;54(2):273-8
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[2]Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome. Science.2001,291(5507):1304-51.
[3]Kμllo IJ, Cooper LT.Early identification of cardiovascμlar risk using genomics and proteomics. Nat Rev Cardiol.2010 Jun;7(6):309-17
[4]McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide association studies for complex traits:consensus, uncertainty and challenges. Nat Rev Genet.2008 May;9(5):356-69.
[5]Hudson TJ, Anderson W, Artez A, et al. International network of cancer genome projects.Nature.2010 Apr 15;464(7291):993-8
[6]Nowell PC, Hungerford DA. A minute chromosome in human granμlocytic leukemia. Science 1960;132:1497.
[7]Moran G, Stokes C, Thewes S, Hube B, Coleman DC, Sμllivan D. Comparative genomics using Candida albicans DNA microarrays reveals absence and divergence of virμlence-associated genes in Candida dubliniensis. Microbiology 2004150 (Pt 10): 3363-3382.
[8]Tyybakinoja A, Elonen E, Piippo K, Porkka K, Knuutila S. Oligonucleotide array-CGH reveals cryptic gene copy number alterations in karyotypically normal acute myeloid leukemia. Leukemia 2007;21 (3):571-574.
[9]Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358(18):1909-1918.
[10]Elaine R.Mardis, Li Ding, Timothy J. Ley, et.al DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome Vol 456 6 November 2008 doi:10.1038/nature07485
[11]D'Andrea AD.Susceptibility pathways in Fanconi's anemia and breast cancer.N Engl J Med.2010 May 20;362(20):1909-19.
[12]Zwijnenburg PJ, Meijers-Heijboer H, Boomsma Dl.Identical but not the same:the value of discordant monozygotic twins in genetic research. Am J Med Genet B Neuropsychiatr Genet.2010 Sep;153B(6):1134-49.
[13]Bergmann AK, Campagna DR, McLoughlin EM, et al. Systematic Molecμlar Genetic Analysis of Congenital Sideroblastic Anemia:Evidence for Genetic Heterogeneity and Identification of Novel Mutations. Pediatr Blood Cancer.2010 Feb;54(2):273-8
[14]Chin L, Andersen JN, Futreal PA.Cancer genomics:from discovery science to personalized medicine. Nat Med.2011 Mar;17(3):297-303.
[1]Jacquemont C,Taniguchi T. The fanconi anemia pathway and ubiquitin[J].BMC Biochem,2007,8 Suppl 1:S10.
[2]Callen E, Casado JA, Tischkowitz MD, et al.A common founder mutation in FANCA underlies the world's highest prevalence of fanconi anemia in Gypsy families from Spain [J].Blood 2005,105 (5):1946-1949.
[3]Giampietro PF, Adler Brecher B, Verlander PC, et al. The need for more accurate and timely diagnosis in fanconi anemia:a report from the International fanconi Anemia Registry. Pediatrics 1993,91(11)16-20.
[4]Auerbach AD. Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp Hematol 1993;21:731-733.
[5]Giampietro PF, Verlander PC, Davis JG, et al. Diagnosis of fanconi anemia in patients without congenital malformations:an International fanconi Anemia Registry study. Am J Med Genet1997,68:58-61.
[6]Giampietro PF, Verlander PC, Maschan A, et al. Fanconi anemia:A model for somatic gene mutation during development. Am J Med Genet 1994,52:36-37
[7]Kutler DI, Singh B, Satagopan J, et al. A 20-year perspective of The International fanconi Anemia Registry (IFAR). Blood 2003;101:1249-1256.
[8]D'Andrea AD.Susceptibility pathways infanconi's anemia and breast cancer.N Engl J Med.2010 May 20;362(20):1909-19.
[9]StoepkeNat Genet, r C, Hain K, Schuster B,et al.SLX4, a coordinator of structure-specific endonucleases, is mutated in a new fanconi anemia subtype.2011 Feb;43(2):138-41. Epub 2011 Jan 16
[10]Vaz F, Hanenberg H, Schuster B.et al. Mutation of the RAD51C gene in a fanconi anemia-like disorder. Nat Genet.2010 May; 42(5):406-9. Epub 2010 Apr 18
[11]Garcia-Higuera, T. Taniguchi, S. Ganesan, et al. Interaction of the fanconi anemia proteins and BRCA1 in a common pathway, Mol. Cell 7 (2001) 249-262.
[12]A.R. Meetei, J.P. de Winter, A.L. Medhurst,et al. A novel ubiquitin ligase is deficient in fanconi anemia, Nat. Genet.35 (2003)165-170.
[13]X. Wang, P.R. Andreassen, D'Andrea, Functional interaction of monoubiq-uitinated FANCD2 and BRCA2/FANCD1 in chromatin, Mol. Cell. Biol.24 (2004) 5850-5862.
[14]Kalindi Parmara, Alan D'Andreaa, Laura J. Niedernhofer. Mouse models of fanconi anemia. Mutation Research 668 (2009) 133-140.
[15]B. Freie, X. Li, S.L. Ciccone, et al. Fanconi anemia type C and p53 cooperate in apoptosis and tumorigenesis, Blood 102 (2003) 4146-4152
[16]M.A. Whitney, G. Royle, M.J. Low, et al. Germ cell defects and hematopoietic hypersensitivity to gamma-interferon in mice with a targeted disruption of the fanconi anemia C gene, Blood 88 (1996)49-58
[17]张之南,沈悌.《血液病诊断及疗效标准》[M].北京：科学出版社,2007：24-25
[18]Auerbach AD. Fanconi anemia and its diagnosis.utat Res.2009,31;668(1-2):4-10.
[19]Raya A, Rodriguez-Piza I, Guenechea G, et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells.Nature.2009;460 (7251):53-9.
[1]Chowdhury T,Brady HJ.Insights from clinical studies into the role of the MLL gene in infant and childhood leukemia.Blood Cells MolDis,2008,40:192-199.
[2]Marschalek R, Nilson I, L"ochner K, et al. The structure of the human ALL21/MLL /HRX gene. Leuk Lymphoma,1997,27:4172428.
[3]Nilson I, L"ochner K, Siegler G, et al. Exon/intron structure of the human ALL21 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukaemias. Br J Haematol,1996,93:9662972.
[4]Meyer C, R Marschalek. LDI-PCR:identification of known and unknown gene fusions of the human MLL gene. Methods Mol Biol.2009;538:71-83.
[5]Marschalek, R. Mechanisms of leukemogenesis by MLL fusion proteins. Br J Haematol.2011 Jan;152(2):141-54
[6]Gale KB, Ford AM,Repp R, et al.Backtracking leukemia to birth:Identification of clonotypic gene fusion sequences in neonatal blood spots [J]. Proc Natl Acad Sci USA,1997,94(25):13950-13954.
[7]Greaves MF Biological models for leukaemia and lymphoma [J]. IA RC Sci Publ,2004,157:351-372.
[8]Krivtsov AV, Feng Z, Lemieux ME,et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell.2008 Nov 4;14(5):355-68.
[9]Steven H Swerdlow, Elias Campo,Nancy Lee Harris,et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues[M]. Lyon,France,Internationl Agency for Research on Cancer.2008:29.
[10]Pallisgaard N, Hokland P, et al.. "Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia." Blood 92(2):574-588.
[11]Claus Meyer,Rolf Marschalek. LDI-PCR:Identification of Known and Unknown Gene Fusions of the Human MLL Gene. Leukemia, Methods in Molecular Biology, 2009(538):71-83.
[12]Maureen D, Megonigal, Eric F, et al. Panhandle PCR for Cdna:A rapid method for isolation of MLL fusion transcripts involving unknown partner genes.PNAS, 2000,97(17):9597-9602.
[13]Brian V, BalgobindC, Michel Zwaan,et al. NRIP3:a novel translocation partner of MLL detected in a pediatric acute myeloid leukemia with complex chromosome 11 rearrangements. Haematologica,2009; 94(7):1033-1034
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