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Author | Li If you ask which type of stem cell is the most "hard" in the body, it must be hematopoietic stem cells.
Hundreds of billions of blood cells are differentiated from hematopoietic stem cells every day
.
Hematopoietic stem cells need to self-renew to maintain the number of their own cell pools while maintaining the production of a large number of blood cells.
Therefore, as they age, "hard" hematopoietic stem cells accumulate a lot of somatic mutations
.
Fortunately, most of these mutations are insignificant, however some of these mutations confer clonal proliferative advantages in hematopoietic stem cells, resulting in clonal hematopoiesis of indeterminant potential (CHIP)
.
The most common of these "some mutations" occur in two epigenes, DNMT3A and TET2.
Mutations in these two genes are also common in myelodysplastic syndrome (MDS), acute myeloid leukemia (acute myeloid leukemia, AML) and myeloproliferative neoplasms (myeloproliferative neoplasms, MPN) these myeloid malignancies
.
It has been clinically found that carrying CHIP-related mutations can increase the risk of subsequent myeloid tumors, and it has also been determined in mouse models that DNMT3A and TET2 inactivating mutations lead to hematopoietic stem progenitor cells.
The risk of malignancy, but the frequency of leukemia is still relatively low, so this also shows that in addition to these CHIP-related mutations such as DNMT3A and TET2, there are some factors (such as secondary mutations) involved in pre-leukemia hematopoietic stem progenitors Malignant transformation of cells
.
Recently, Daniel T.
Starczynowski of Cincinnati Children's Hospital and Iannis Aifantis of New York University School of Medicine published an article in Cell Stem Cell TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity, revealing that TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity.
Loss-of-function promotes the development of myeloid malignancies by regulating the proto-oncogene MYC
.
As mentioned earlier, TET2 is a common mutation in pre-leukemic hematopoietic stem cells.
To search for secondary mutations required for malignant transformation, the researchers used RNAi screening to treat Tet2-/-lineage-cKit+ hematopoietic stem progenitor cells.
Bone marrow transplantation, it was found that the loss of TRAF6 function will cooperate with Tet2 mutation to make it develop into malignancy
.
Next, the researchers constructed TRAF6 and TET2 double-knockout mice and used the VavCre and Mix1Cre systems to demonstrate that double-knockout LSK cells (i.
e.
hematopoietic stem progenitor cells) can proliferate clonally in vitro and in vivo, and proved that TRAF only works in CHIP-related gene mutations (such as TET2) can promote the malignant transformation of pre-leukemia hematopoietic stem progenitor cells
.
Mouse models demonstrate synergy between TRAF6 and TET2, so what about TRAF6 in human myeloid malignancies? The researchers mined public databases and found that the frequency of TRAF6 copy number deletions in acute myeloid leukemia (AML) was only 3%, and the mutation frequency was only 1%, but 30% of AML patients showed decreased mRNA levels
.
So what factors affect the mRNA expression of TRAF6? The researchers found that the promoter of TRAF6 was hypermethylated, and a similar phenomenon was also found in MPN
.
So is the methylation status of TRAF6 related to mutations in TET2 (TET2 happens to be a demethylase)? After knocking out TET2, no change in TRAF6 expression was found
.
This result also shows that TRAF6 is affected by other factors
.
After further analysis, TRAF6 expression was found to be related to FLT3-ITD (internal tandem duplication) mutation
.
Therefore, the researchers used a mouse model to prove that high expression of TRAF6 can prolong the survival of FLT3-ITD mice, revealing that TRAF6 can act as a tumor suppressor gene in a special context
.
After determining the upstream relationship of TRAF6, what about the downstream pathway of TRAF6? The researchers performed RNAseq on TRAF6TET2 double-knockout LSK cells and found that MYC-related genes were up-regulated, and this up-regulation only existed in TRAF6-deficient or double-deletion LSK cells, but not in TET2-deficient cells, indicating that these genes are not Affected by TET2, but by TRAF6
.
To prove the relationship between TRAF6-MYC, the researchers treated TRAF6TET2 double-knockout LSK cells with MYC-Max dimerization inhibitor, and found that their in vitro cloning ability was inhibited, and this was further demonstrated by transplantation experiments
.
So how does TRAF6 affect MYC-related genes? TRAF6 is an E3 ubiquitin ligase (writing here, readers will turn to the above again, in the third paragraph, it is written that the author conducted RNAi screening, how were these shRNAs selected? The researchers chose to target ubiquitin It is not surprising that the E3 ubiquitin ligase TRAF6 was screened for the shRNA of proteasome-related genes), not surprisingly, the researchers proved that TRAF6 can ubiquitinate MYC through K148, and found that at the K148 site, There is a competitive relationship between ubiquitination and acetylation.
When TRAF6 is depleted, MYCK148 cannot be ubiquitinated, thereby increasing acetylation, promoting MYC proto-oncofunction, and further promoting the development of AML
.
In conclusion, this study revealed that TRAF6, as a tumor suppressor protein, can promote the transformation of pre-leukemia cells to malignant tumors by regulating Myc in the presence of CHIP mutations
.
However, there are still some unanswered questions in this study, such as whether reduced TRAF6 expression and TET2 mutation are sufficient to cause leukemia in humans; whether TRAF6 is also related to other CHIP mutations; the relationship between FLT3-ITD and TRAF6; MYCK148 acetylation and The relationship between MYC functions and more
.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
12.
007 Publisher: 11th reprint notice [Original article] BioArt original article, welcome to forward and share personally, reprint is prohibited without permission, all published articles The copyright of the work is owned by BioArt
.
BioArt reserves all legal rights and violators will be held accountable
.
Hundreds of billions of blood cells are differentiated from hematopoietic stem cells every day
.
Hematopoietic stem cells need to self-renew to maintain the number of their own cell pools while maintaining the production of a large number of blood cells.
Therefore, as they age, "hard" hematopoietic stem cells accumulate a lot of somatic mutations
.
Fortunately, most of these mutations are insignificant, however some of these mutations confer clonal proliferative advantages in hematopoietic stem cells, resulting in clonal hematopoiesis of indeterminant potential (CHIP)
.
The most common of these "some mutations" occur in two epigenes, DNMT3A and TET2.
Mutations in these two genes are also common in myelodysplastic syndrome (MDS), acute myeloid leukemia (acute myeloid leukemia, AML) and myeloproliferative neoplasms (myeloproliferative neoplasms, MPN) these myeloid malignancies
.
It has been clinically found that carrying CHIP-related mutations can increase the risk of subsequent myeloid tumors, and it has also been determined in mouse models that DNMT3A and TET2 inactivating mutations lead to hematopoietic stem progenitor cells.
The risk of malignancy, but the frequency of leukemia is still relatively low, so this also shows that in addition to these CHIP-related mutations such as DNMT3A and TET2, there are some factors (such as secondary mutations) involved in pre-leukemia hematopoietic stem progenitors Malignant transformation of cells
.
Recently, Daniel T.
Starczynowski of Cincinnati Children's Hospital and Iannis Aifantis of New York University School of Medicine published an article in Cell Stem Cell TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity, revealing that TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity.
Loss-of-function promotes the development of myeloid malignancies by regulating the proto-oncogene MYC
.
As mentioned earlier, TET2 is a common mutation in pre-leukemic hematopoietic stem cells.
To search for secondary mutations required for malignant transformation, the researchers used RNAi screening to treat Tet2-/-lineage-cKit+ hematopoietic stem progenitor cells.
Bone marrow transplantation, it was found that the loss of TRAF6 function will cooperate with Tet2 mutation to make it develop into malignancy
.
Next, the researchers constructed TRAF6 and TET2 double-knockout mice and used the VavCre and Mix1Cre systems to demonstrate that double-knockout LSK cells (i.
e.
hematopoietic stem progenitor cells) can proliferate clonally in vitro and in vivo, and proved that TRAF only works in CHIP-related gene mutations (such as TET2) can promote the malignant transformation of pre-leukemia hematopoietic stem progenitor cells
.
Mouse models demonstrate synergy between TRAF6 and TET2, so what about TRAF6 in human myeloid malignancies? The researchers mined public databases and found that the frequency of TRAF6 copy number deletions in acute myeloid leukemia (AML) was only 3%, and the mutation frequency was only 1%, but 30% of AML patients showed decreased mRNA levels
.
So what factors affect the mRNA expression of TRAF6? The researchers found that the promoter of TRAF6 was hypermethylated, and a similar phenomenon was also found in MPN
.
So is the methylation status of TRAF6 related to mutations in TET2 (TET2 happens to be a demethylase)? After knocking out TET2, no change in TRAF6 expression was found
.
This result also shows that TRAF6 is affected by other factors
.
After further analysis, TRAF6 expression was found to be related to FLT3-ITD (internal tandem duplication) mutation
.
Therefore, the researchers used a mouse model to prove that high expression of TRAF6 can prolong the survival of FLT3-ITD mice, revealing that TRAF6 can act as a tumor suppressor gene in a special context
.
After determining the upstream relationship of TRAF6, what about the downstream pathway of TRAF6? The researchers performed RNAseq on TRAF6TET2 double-knockout LSK cells and found that MYC-related genes were up-regulated, and this up-regulation only existed in TRAF6-deficient or double-deletion LSK cells, but not in TET2-deficient cells, indicating that these genes are not Affected by TET2, but by TRAF6
.
To prove the relationship between TRAF6-MYC, the researchers treated TRAF6TET2 double-knockout LSK cells with MYC-Max dimerization inhibitor, and found that their in vitro cloning ability was inhibited, and this was further demonstrated by transplantation experiments
.
So how does TRAF6 affect MYC-related genes? TRAF6 is an E3 ubiquitin ligase (writing here, readers will turn to the above again, in the third paragraph, it is written that the author conducted RNAi screening, how were these shRNAs selected? The researchers chose to target ubiquitin It is not surprising that the E3 ubiquitin ligase TRAF6 was screened for the shRNA of proteasome-related genes), not surprisingly, the researchers proved that TRAF6 can ubiquitinate MYC through K148, and found that at the K148 site, There is a competitive relationship between ubiquitination and acetylation.
When TRAF6 is depleted, MYCK148 cannot be ubiquitinated, thereby increasing acetylation, promoting MYC proto-oncofunction, and further promoting the development of AML
.
In conclusion, this study revealed that TRAF6, as a tumor suppressor protein, can promote the transformation of pre-leukemia cells to malignant tumors by regulating Myc in the presence of CHIP mutations
.
However, there are still some unanswered questions in this study, such as whether reduced TRAF6 expression and TET2 mutation are sufficient to cause leukemia in humans; whether TRAF6 is also related to other CHIP mutations; the relationship between FLT3-ITD and TRAF6; MYCK148 acetylation and The relationship between MYC functions and more
.
Original link: https://doi.
org/10.
1016/j.
stem.
2021.
12.
007 Publisher: 11th reprint notice [Original article] BioArt original article, welcome to forward and share personally, reprint is prohibited without permission, all published articles The copyright of the work is owned by BioArt
.
BioArt reserves all legal rights and violators will be held accountable
.
