克隆造血解读
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N Engl J Med 2002;346: 564-9. N Engl J Med 2008;359:575-83.
Clonal Hematopoiesis
• We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes.
Clonal Hematopoiesis
• 693 of 746 persons with a detectable mutation had only one mutation in the set of genes examined , a finding that was consistent with the hypothesis that these persons had clones harboring only an initiating lesion.
Clonal Hematopoiesis
Clonal Hematopoiesis
• Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age.
variation (and therefore disease)
Morgan et al. Nat Genetics 23, 314 (1999)
Epigenetics
Aging HSCs in both mice and humans also exhibit broad changes in their methylomes, and loss-of-function mutations in the regulators of DNA methylation.
Aging, Hematopoiesis, Premalignant state
( pre-MDS, pre-AML )
Jiangsu Province Hospital First Affiliated Hospital Nanjing Medical University Guangsheng He (何广胜) heguangsheng1972@sina.com
3
Epigenetics
• Mitotically stable changes in gene expression
• One genome, >200 cell types: • Epigenetics is a key determinant of cellular
identity • Epigenetics can also mediate phenotypic
Clonal Hematopoiesis
• The most commonly mutated gene was DNMT3A (403 variants) , followed by TET2 (72 variants) and ASXL1 (62 variants). Other frequently mutated genes included TP53 (33 variants), JAK2 (31 variants), and SF3B1 (27 variants).
• (pre-AML group), • Together with 414 unselected age- and
gendermatched individuals (control group).
ARCH with putative driver (PD) mutations, was found in 73.4% of the pre-AML cases at a median of 7.6 years before diagnosis. By contrast, ARCH-PD was observed in 36.7% of controls.
Bejar R, et al. Leukemia. 2017 Sep;31(9):1869-1871.
突变数量和丰度
相对低危MDS
相对高危MDS
CHIP/Tx - CHIP在髓细胞毒性治疗中的情况下; CCUS -意义未明克隆性血细胞减少症; LR-MDS - 风险较低的骨髓增生异常综合征; HR-MDS - 风险较高的骨髓增生异常综合征; AML - 急性粒细胞白血病; sAML - 继发性急性髓系白血病。
• For 10 mutations, the variant allele fraction stayed the same or decreased slightly, and for 7 mutations, the variant allele fraction increased;
• New mutations were detected in 2 persons. However, none of the 13 persons had a hematologic cancer.
Nature, 2018, https://doi.org/10.1038/s41586-018-0317-6
Prediction of acute myeloid leukaemia risk in healthy individuals
• Deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign as age-related clonal haematopoiesis ( ARCH ).
Prediction of acute myeloid leukaemia risk in healthy individuals
• We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis
• 4 to 8 years after the initial DNA collection.
Clonal Hematopoiesis
• In all cases, the mutations detected at the earlier time point were still present at the later time point.
• Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively.
Clonal Hematopoiesis
The most common base-pair change in the somatic variants was a cytosine-to-thymine (C→T) transition , which is considered to be a somatic mutational signature of aging.
Clone
• Single cell • Self-renew • Proliferation
• Cancer is thought to arise through the stepwise acquisition of genetic or epigenetic changes that transform a normal cell.
Progression of MDS
无克隆异常
无Biblioteka Baidu床异常
具有可能致癌的条件
克隆性疾病
晚期恶性肿瘤
癌症风险
ncICUS – 非克隆性意义未明的特发性血细胞减少症; ARCH - 老化相关的克隆性造血作用; CHIP -意义未明的克隆性造血; CHIP/AA - CHIP在再生障碍性贫血中的情况下; CHIP/FP - CHIP在MDS或AML的家族倾向的情况下;
Clonal Hematopoiesis
• Persistence of Somatic Mutations over Time. Not means cancer will happended.
• 13 persons with 17 somatic mutations(4 persons had 2 mutations).
Clonal Hematopoiesis
Prediction of acute myeloid leukaemia risk in healthy individuals
• Recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis.
Clone
• For example:
• Multiple myeloma is frequently preceded by monoclonal gammopathy of unknown significance (MGUS).
• Chronic lymphocytic leukemia is commonly preceded by monoclonal B-cell lymphocytosis.
• We looked for somatic mutations by identifying previously characterized singlenucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers.
The median number of ARCH-PD mutations per individual increased with age and was significantly higher in the pre-AML group relative to controls
Although persons with detectable mutations had a markedly increased risk of hematologic cancer, the absolute risk remained small; overall, a hematologic cancer developed during the study period in approximately 4% of persons with a mutation . This translates to a risk of hematologic cancer of approximately 0.5% per year overall and approximately 1% per year among persons.
Clonal Hematopoiesis
• We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes.
Clonal Hematopoiesis
• 693 of 746 persons with a detectable mutation had only one mutation in the set of genes examined , a finding that was consistent with the hypothesis that these persons had clones harboring only an initiating lesion.
Clonal Hematopoiesis
Clonal Hematopoiesis
• Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age.
variation (and therefore disease)
Morgan et al. Nat Genetics 23, 314 (1999)
Epigenetics
Aging HSCs in both mice and humans also exhibit broad changes in their methylomes, and loss-of-function mutations in the regulators of DNA methylation.
Aging, Hematopoiesis, Premalignant state
( pre-MDS, pre-AML )
Jiangsu Province Hospital First Affiliated Hospital Nanjing Medical University Guangsheng He (何广胜) heguangsheng1972@sina.com
3
Epigenetics
• Mitotically stable changes in gene expression
• One genome, >200 cell types: • Epigenetics is a key determinant of cellular
identity • Epigenetics can also mediate phenotypic
Clonal Hematopoiesis
• The most commonly mutated gene was DNMT3A (403 variants) , followed by TET2 (72 variants) and ASXL1 (62 variants). Other frequently mutated genes included TP53 (33 variants), JAK2 (31 variants), and SF3B1 (27 variants).
• (pre-AML group), • Together with 414 unselected age- and
gendermatched individuals (control group).
ARCH with putative driver (PD) mutations, was found in 73.4% of the pre-AML cases at a median of 7.6 years before diagnosis. By contrast, ARCH-PD was observed in 36.7% of controls.
Bejar R, et al. Leukemia. 2017 Sep;31(9):1869-1871.
突变数量和丰度
相对低危MDS
相对高危MDS
CHIP/Tx - CHIP在髓细胞毒性治疗中的情况下; CCUS -意义未明克隆性血细胞减少症; LR-MDS - 风险较低的骨髓增生异常综合征; HR-MDS - 风险较高的骨髓增生异常综合征; AML - 急性粒细胞白血病; sAML - 继发性急性髓系白血病。
• For 10 mutations, the variant allele fraction stayed the same or decreased slightly, and for 7 mutations, the variant allele fraction increased;
• New mutations were detected in 2 persons. However, none of the 13 persons had a hematologic cancer.
Nature, 2018, https://doi.org/10.1038/s41586-018-0317-6
Prediction of acute myeloid leukaemia risk in healthy individuals
• Deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign as age-related clonal haematopoiesis ( ARCH ).
Prediction of acute myeloid leukaemia risk in healthy individuals
• We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis
• 4 to 8 years after the initial DNA collection.
Clonal Hematopoiesis
• In all cases, the mutations detected at the earlier time point were still present at the later time point.
• Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively.
Clonal Hematopoiesis
The most common base-pair change in the somatic variants was a cytosine-to-thymine (C→T) transition , which is considered to be a somatic mutational signature of aging.
Clone
• Single cell • Self-renew • Proliferation
• Cancer is thought to arise through the stepwise acquisition of genetic or epigenetic changes that transform a normal cell.
Progression of MDS
无克隆异常
无Biblioteka Baidu床异常
具有可能致癌的条件
克隆性疾病
晚期恶性肿瘤
癌症风险
ncICUS – 非克隆性意义未明的特发性血细胞减少症; ARCH - 老化相关的克隆性造血作用; CHIP -意义未明的克隆性造血; CHIP/AA - CHIP在再生障碍性贫血中的情况下; CHIP/FP - CHIP在MDS或AML的家族倾向的情况下;
Clonal Hematopoiesis
• Persistence of Somatic Mutations over Time. Not means cancer will happended.
• 13 persons with 17 somatic mutations(4 persons had 2 mutations).
Clonal Hematopoiesis
Prediction of acute myeloid leukaemia risk in healthy individuals
• Recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis.
Clone
• For example:
• Multiple myeloma is frequently preceded by monoclonal gammopathy of unknown significance (MGUS).
• Chronic lymphocytic leukemia is commonly preceded by monoclonal B-cell lymphocytosis.
• We looked for somatic mutations by identifying previously characterized singlenucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers.
The median number of ARCH-PD mutations per individual increased with age and was significantly higher in the pre-AML group relative to controls
Although persons with detectable mutations had a markedly increased risk of hematologic cancer, the absolute risk remained small; overall, a hematologic cancer developed during the study period in approximately 4% of persons with a mutation . This translates to a risk of hematologic cancer of approximately 0.5% per year overall and approximately 1% per year among persons.