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Hereditary aplastic anemia is a common and difficult disease in pediatrics.
Most patients eventually develop leukemia.
The pathological mechanism has not yet been elucidated.
In a previous study, the team of KJ Patel from the University of Cambridge in the United Kingdom and the team from Takada Tsutomu of Kyoto University in Japan jointly reported a new type of dysplastic anemia [1] in the Mol Cell magazine on November 3, 2020.
The patients appeared at the same time.
The mutation of ALDH2 (Aldehyde Dehydrogenase 2, acetaldehyde dehydrogenase 2) and ADH5 (Alcohol Dehydrogenase 5, alcohol dehydrogenase 5) causes the formaldehyde produced in the process of hematopoietic differentiation cannot be decomposed normally, DNA damage is accumulated, and then induced Aplastic anemia occurs and eventually develops into leukemia.
It is understood that the author named this type of "ADH5/ALDH2 dysfunction" "Aldehyde Degradation Deficiency (ADD) Syndrome" [Aldehyde Degradation Deficiency (ADD) Syndrome].
Recently, Takata Takata's team from Kyoto University in Japan published a long research article titled Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia–like IBMFS ADH5/ALDH2 deficiency in the Blood journal.
Through CRISPR/Cas9 gene editing technology and in vitro hematopoietic cell differentiation and other technical means, it is revealed how ADH5/ALDH2 metabolizes formaldehyde during the differentiation of human hematopoietic stem cells to prevent hematopoietic stem cells from being damaged.
Professor MinoruTakata is the corresponding author of this article, and Dr.
Anfeng Mou is the first author.The authors first found that after adding an ADH5 inhibitor to lymphocytes carrying ALDH2 gene mutations (derived from normal humans), sister chromatid exchanges (SCEs) were significantly increased.
Interestingly, in the HAP1 cell line (from patients with chronic leukemia), even if the ADH5/ALDH2 gene is knocked out, it will not have any effect on the cells, but only 0.
5μM formaldehyde can significantly increase SCE, while SCE An increase represents an increase in DNA damage.
At the same time, in the cytotoxicity test experiment, the knockout of ALHD2 in cells alone did not lead to increased mortality due to the toxicity of formaldehyde, but in the case of ADH5 deficiency, ALDH2 is very important for the metabolism of formaldehyde.
This finding reveals The synergistic effect of ADH5 and ALDH2 in the process of formaldehyde metabolism.
In addition, the author uses cell reprogramming technology to transform the patient’s skin cells into induced pluripotent stem cells (iPSCs), and uses CRISPR/Cas9 technology to replenish the defective ADH5 gene into the patient’s iPS cells.
This replenishment system can be used by doxycycline.
(DOX) Induces the expression of ADH5.
At the same time, the author made ADH5/ALDH2 knockout cells based on the 201B7-iPS cell line as a control.
The results of in vitro hematopoietic cell differentiation experiments showed that the knockout of ADH5 or ALDH2 gene alone had little effect on the formation of hematopoietic colony, but the double knockout of ADH5/ALDH2 resulted in almost no survival of hematopoietic stem cell colonies.
In patients with both ADH5 and ALDH2 gene defects, their iPS cells can hardly form a complete hematopoietic stem cell colony (colony), and the degree of DNA damage at the hematopoietic progenitor cell stage is high, but the expression of ADH5 saves this to a large extent phenomenon.
In addition, the new ALDH2 activator C1 can promote hematopoietic differentiation to a certain extent and relieve symptoms.
Further research found that the ADH5/ALDH2 defect hindered the differentiation of CD34+ cells (hematopoietic stem cells) to CD45+ (mature blood cells).
In the differentiation process of mature blood cells, the accumulation of DNA damage can be observed in the case of ADH5 or ALDH2 single knockout, which proves the continuous production of formaldehyde during hematopoietic differentiation.
The study confirmed that ADH5/ALDH2 defects can lead to a large amount of formaldehyde accumulation in hematopoietic differentiation, which in turn causes excessive DNA damage, and the degree of damage exceeds the ability of DNA repair.
Combined with the research of other teams [2], these findings may explain the pathogenesis of Fanconi anemia.
ALDH2 is a very important metabolic enzyme in the metabolism of acetaldehyde (a secondary metabolite of alcohol).
Mutations in this gene can cause a sudden decrease in the ability to decompose acetaldehyde.
A common feature is redness after drinking.
About ~40% of people in China and ~50% in Japan have ALDH2 mutations, and ~40% of the population in East Asia have ALDH2 mutations.
This research shows that ALDH2 also has a strong formaldehyde decomposition ability.
The results of this study indicate that common formaldehyde metabolism gene mutations may be an important cause of hereditary blood diseases.
In addition, the defect of two aldehyde metabolizing enzyme genes (ADH5/ALDH2) will lead to aplastic anemia.
The research results may bring new breakthroughs in the treatment of leukemia. Original link: https://doi.
org/10.
1182/blood.
2020009111 Plate maker: 11 References 1.
Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.
https://doi.
org/10.
1016 /j.
molcel.
2020.
10.
0122.
A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.
https://doi.
org/10.
1016/j.
molcel.
2020.
11.
040 Reprint Instructions [Non-original article] Copyright of this article Owned by the author of the article, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated.
Most patients eventually develop leukemia.
The pathological mechanism has not yet been elucidated.
In a previous study, the team of KJ Patel from the University of Cambridge in the United Kingdom and the team from Takada Tsutomu of Kyoto University in Japan jointly reported a new type of dysplastic anemia [1] in the Mol Cell magazine on November 3, 2020.
The patients appeared at the same time.
The mutation of ALDH2 (Aldehyde Dehydrogenase 2, acetaldehyde dehydrogenase 2) and ADH5 (Alcohol Dehydrogenase 5, alcohol dehydrogenase 5) causes the formaldehyde produced in the process of hematopoietic differentiation cannot be decomposed normally, DNA damage is accumulated, and then induced Aplastic anemia occurs and eventually develops into leukemia.
It is understood that the author named this type of "ADH5/ALDH2 dysfunction" "Aldehyde Degradation Deficiency (ADD) Syndrome" [Aldehyde Degradation Deficiency (ADD) Syndrome].
Recently, Takata Takata's team from Kyoto University in Japan published a long research article titled Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia–like IBMFS ADH5/ALDH2 deficiency in the Blood journal.
Through CRISPR/Cas9 gene editing technology and in vitro hematopoietic cell differentiation and other technical means, it is revealed how ADH5/ALDH2 metabolizes formaldehyde during the differentiation of human hematopoietic stem cells to prevent hematopoietic stem cells from being damaged.
Professor MinoruTakata is the corresponding author of this article, and Dr.
Anfeng Mou is the first author.The authors first found that after adding an ADH5 inhibitor to lymphocytes carrying ALDH2 gene mutations (derived from normal humans), sister chromatid exchanges (SCEs) were significantly increased.
Interestingly, in the HAP1 cell line (from patients with chronic leukemia), even if the ADH5/ALDH2 gene is knocked out, it will not have any effect on the cells, but only 0.
5μM formaldehyde can significantly increase SCE, while SCE An increase represents an increase in DNA damage.
At the same time, in the cytotoxicity test experiment, the knockout of ALHD2 in cells alone did not lead to increased mortality due to the toxicity of formaldehyde, but in the case of ADH5 deficiency, ALDH2 is very important for the metabolism of formaldehyde.
This finding reveals The synergistic effect of ADH5 and ALDH2 in the process of formaldehyde metabolism.
In addition, the author uses cell reprogramming technology to transform the patient’s skin cells into induced pluripotent stem cells (iPSCs), and uses CRISPR/Cas9 technology to replenish the defective ADH5 gene into the patient’s iPS cells.
This replenishment system can be used by doxycycline.
(DOX) Induces the expression of ADH5.
At the same time, the author made ADH5/ALDH2 knockout cells based on the 201B7-iPS cell line as a control.
The results of in vitro hematopoietic cell differentiation experiments showed that the knockout of ADH5 or ALDH2 gene alone had little effect on the formation of hematopoietic colony, but the double knockout of ADH5/ALDH2 resulted in almost no survival of hematopoietic stem cell colonies.
In patients with both ADH5 and ALDH2 gene defects, their iPS cells can hardly form a complete hematopoietic stem cell colony (colony), and the degree of DNA damage at the hematopoietic progenitor cell stage is high, but the expression of ADH5 saves this to a large extent phenomenon.
In addition, the new ALDH2 activator C1 can promote hematopoietic differentiation to a certain extent and relieve symptoms.
Further research found that the ADH5/ALDH2 defect hindered the differentiation of CD34+ cells (hematopoietic stem cells) to CD45+ (mature blood cells).
In the differentiation process of mature blood cells, the accumulation of DNA damage can be observed in the case of ADH5 or ALDH2 single knockout, which proves the continuous production of formaldehyde during hematopoietic differentiation.
The study confirmed that ADH5/ALDH2 defects can lead to a large amount of formaldehyde accumulation in hematopoietic differentiation, which in turn causes excessive DNA damage, and the degree of damage exceeds the ability of DNA repair.
Combined with the research of other teams [2], these findings may explain the pathogenesis of Fanconi anemia.
ALDH2 is a very important metabolic enzyme in the metabolism of acetaldehyde (a secondary metabolite of alcohol).
Mutations in this gene can cause a sudden decrease in the ability to decompose acetaldehyde.
A common feature is redness after drinking.
About ~40% of people in China and ~50% in Japan have ALDH2 mutations, and ~40% of the population in East Asia have ALDH2 mutations.
This research shows that ALDH2 also has a strong formaldehyde decomposition ability.
The results of this study indicate that common formaldehyde metabolism gene mutations may be an important cause of hereditary blood diseases.
In addition, the defect of two aldehyde metabolizing enzyme genes (ADH5/ALDH2) will lead to aplastic anemia.
The research results may bring new breakthroughs in the treatment of leukemia. Original link: https://doi.
org/10.
1182/blood.
2020009111 Plate maker: 11 References 1.
Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans.
https://doi.
org/10.
1016 /j.
molcel.
2020.
10.
0122.
A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.
https://doi.
org/10.
1016/j.
molcel.
2020.
11.
040 Reprint Instructions [Non-original article] Copyright of this article Owned by the author of the article, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated.
