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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, and interested parties.
Long press or scan the QR code below to follow us
.
The recurrence of patients with iNature chronic myeloid leukemia (CML) may be at least partly due to the lack of sensitivity of leukemia stem cells (LSC) to tyrosine kinase inhibitors (TKI) such as imatinib
.
The precise adjustment of LSC dryness is not fully understood
.
Given that the traits of LSCs are under epigenetic regulation, it is hypothesized that LSCs may depend on the continuous active transcription of genes related to super enhancers (SEs), which in turn may indicate an opportunity for intervention
.
On September 22, 2021, Pan Jingxuan of Sun Yat-sen University and Jin Yanli of Jinan University (Jinan University as the first unit) jointly published an online newsletter entitled "Super-enhancer landscape reveals leukemia stem cell reliance on X" in Science Translational Medicine (IF=18) -box binding protein 1 as a therapeutic vulnerability" research paper, which tested this hypothesis and described the SE landscape in LSC of CML patients
.
THZ1 (Cyclin-dependent kinase 7 (CDK7) inhibitor) disrupts the transcription of SE-related genes and can effectively eradicate LSC in CML mice driven by retrovirus BCR-ABL, while retaining normal hematopoietic stem cells
.
In addition, the study found that X-box binding protein 1 (XBP1) is the substrate of mRNA splicing endonuclease IRE1α in the unfolded protein reaction pathway, and is an oncogene related to SE in LSC
.
Knockout of XBP1 will reduce the survival rate and self-renewal ability of primary CML CD34+ cells, and eradicate LSC in CML mice
.
Conditional knockout of Ire1 specific to hematopoietic cells selectively blocks the production of spliced forms of Xbp1, which can inhibit the progression of CML and impair the occurrence of leukemia in CML mice with LSC
.
Overall, the study identified the epigenetic transcription program in LSC, added evidence to the "oncogene addiction" theory, and proposed a potential targeting strategy for CML
.
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease caused by the malignant transformation of hematopoietic stem cells (HSC), which produces the BCR-ABL fusion gene through a translocation between chromosomes 9q34 and 22q11.
2
.
The truncated chromosome 22 contains a chromosome 9 called the Philadelphia chromosome (Ph).
The fusion oncogene encodes the tyrosine kinase BCR-ABL oncoprotein, which is necessary for the occurrence and maintenance of CML
.
The discovery of ABL-specific tyrosine kinase inhibitor (TKI) imatinib brought the treatment of cancers such as CML into the era of targeted therapy, making them controllable diseases
.
However, imatinib resistance and recurrence are clinical challenges, especially for advanced CML in adults and Ph+ acute lymphoblastic leukemia in adolescents
.
An important driver of acquired resistance to imatinib is the occurrence of point mutations such as G250E, Q252H, Y253H, E255K/V and T315I in BCR-ABL.
These point mutations can be controlled by second- and third-generation TKIs
.
However, TKI cannot at least partially cure CML because leukemia stem cells (LSC) do not rely on the catalytic activity of the BCR-ABL tyrosine kinase
.
Despite TKI treatment, LSCs still exist and may cause recurrence
.
Further limitations of using TKI to treat CML include the risk of toxicity, adverse reactions, and the high cost of the treatment itself
.
In addition, imatinib-resistant mutations, especially T315I in BCR-ABL, are not sensitive to second-generation TKIs (such as nilotinib and dasatinib), which may further complicate the setting of LSC
.
An LSC can divide to form an identical daughter cell to maintain the LSC pool (self-renewal) and a daughter cell that can differentiate into a large number of leukemia cells at different stages
.
Identifying the regulators required for LSC self-renewal and survival is the main goal of the CML field
.
Several objectives have been shown to maintain CML LSC, including survival regulators, self-renewal pathway components, epigenetic regulators, metabolic enzymes, and bypass tyrosine kinases
.
However, the precise regulation of LSC dryness is still not fully understood, and clinically available drugs for LSC have not been approved
.
Super-enhancers (SEs) are a large group of closely spaced active enhancers, which are usually related to the maintenance of cell identity through cell-type-specific gene expression
.
SE drives the expression of key oncogenes, such as dwarf-related transcription factor 1 (RUNX1), v-myc avian myeloma virus oncogene neuroblastoma-derived homolog (MYCN), p21 activated kinase 4 (PAK4) and E26 carcinogenesis Gene homolog 2 (ETS2)
.
Since they usually encode products with short half-lives, these SE-related oncogenes exhibit a special dependence on continuous active transcription and may represent a target for intervention in specific cancers before "global" transcription downregulation occurs
.
SE-related transcriptional activation is mediated by factors such as cyclin-dependent kinase 7 (CDK7).
CDK7 promotes transcription initiation and extension through phosphorylation of RNA polymerase II (RNAPII)
.
This activity can be inhibited by THZ1, which is a potent and selective CDK7 covalent inhibitor with a median inhibitory concentration (IC50) of 3.
2 nM
.
THZ1 has been shown to have strong anti-tumor activity against a series of cancers, such as neuroblastoma, small cell lung cancer and triple negative breast cancer
.
The results of this study show that the self-renewal and survival ability of LSC depends to a large extent on the transcription of the gene X-box binding protein 1 (XBP1), which is an oncogene related to SE and is particularly susceptible to SE intervention
.
These findings provide further evidence for the "oncogene addiction" theory and propose potential targeted strategies for the treatment of CML
.
Reference message: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, and interested parties.
Long press or scan the QR code below to follow us
.
The recurrence of patients with iNature chronic myeloid leukemia (CML) may be at least partly due to the lack of sensitivity of leukemia stem cells (LSC) to tyrosine kinase inhibitors (TKI) such as imatinib
.
The precise adjustment of LSC dryness is not fully understood
.
Given that the traits of LSCs are under epigenetic regulation, it is hypothesized that LSCs may depend on the continuous active transcription of genes related to super enhancers (SEs), which in turn may indicate an opportunity for intervention
.
On September 22, 2021, Pan Jingxuan of Sun Yat-sen University and Jin Yanli of Jinan University (Jinan University as the first unit) jointly published an online newsletter entitled "Super-enhancer landscape reveals leukemia stem cell reliance on X" in Science Translational Medicine (IF=18) -box binding protein 1 as a therapeutic vulnerability" research paper, which tested this hypothesis and described the SE landscape in LSC of CML patients
.
THZ1 (Cyclin-dependent kinase 7 (CDK7) inhibitor) disrupts the transcription of SE-related genes and can effectively eradicate LSC in CML mice driven by retrovirus BCR-ABL, while retaining normal hematopoietic stem cells
.
In addition, the study found that X-box binding protein 1 (XBP1) is the substrate of mRNA splicing endonuclease IRE1α in the unfolded protein reaction pathway, and is an oncogene related to SE in LSC
.
Knockout of XBP1 will reduce the survival rate and self-renewal ability of primary CML CD34+ cells, and eradicate LSC in CML mice
.
Conditional knockout of Ire1 specific to hematopoietic cells selectively blocks the production of spliced forms of Xbp1, which can inhibit the progression of CML and impair the occurrence of leukemia in CML mice with LSC
.
Overall, the study identified the epigenetic transcription program in LSC, added evidence to the "oncogene addiction" theory, and proposed a potential targeting strategy for CML
.
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease caused by the malignant transformation of hematopoietic stem cells (HSC), which produces the BCR-ABL fusion gene through a translocation between chromosomes 9q34 and 22q11.
2
.
The truncated chromosome 22 contains a chromosome 9 called the Philadelphia chromosome (Ph).
The fusion oncogene encodes the tyrosine kinase BCR-ABL oncoprotein, which is necessary for the occurrence and maintenance of CML
.
The discovery of ABL-specific tyrosine kinase inhibitor (TKI) imatinib brought the treatment of cancers such as CML into the era of targeted therapy, making them controllable diseases
.
However, imatinib resistance and recurrence are clinical challenges, especially for advanced CML in adults and Ph+ acute lymphoblastic leukemia in adolescents
.
An important driver of acquired resistance to imatinib is the occurrence of point mutations such as G250E, Q252H, Y253H, E255K/V and T315I in BCR-ABL.
These point mutations can be controlled by second- and third-generation TKIs
.
However, TKI cannot at least partially cure CML because leukemia stem cells (LSC) do not rely on the catalytic activity of the BCR-ABL tyrosine kinase
.
Despite TKI treatment, LSCs still exist and may cause recurrence
.
Further limitations of using TKI to treat CML include the risk of toxicity, adverse reactions, and the high cost of the treatment itself
.
In addition, imatinib-resistant mutations, especially T315I in BCR-ABL, are not sensitive to second-generation TKIs (such as nilotinib and dasatinib), which may further complicate the setting of LSC
.
An LSC can divide to form an identical daughter cell to maintain the LSC pool (self-renewal) and a daughter cell that can differentiate into a large number of leukemia cells at different stages
.
Identifying the regulators required for LSC self-renewal and survival is the main goal of the CML field
.
Several objectives have been shown to maintain CML LSC, including survival regulators, self-renewal pathway components, epigenetic regulators, metabolic enzymes, and bypass tyrosine kinases
.
However, the precise regulation of LSC dryness is still not fully understood, and clinically available drugs for LSC have not been approved
.
Super-enhancers (SEs) are a large group of closely spaced active enhancers, which are usually related to the maintenance of cell identity through cell-type-specific gene expression
.
SE drives the expression of key oncogenes, such as dwarf-related transcription factor 1 (RUNX1), v-myc avian myeloma virus oncogene neuroblastoma-derived homolog (MYCN), p21 activated kinase 4 (PAK4) and E26 carcinogenesis Gene homolog 2 (ETS2)
.
Since they usually encode products with short half-lives, these SE-related oncogenes exhibit a special dependence on continuous active transcription and may represent a target for intervention in specific cancers before "global" transcription downregulation occurs
.
SE-related transcriptional activation is mediated by factors such as cyclin-dependent kinase 7 (CDK7).
CDK7 promotes transcription initiation and extension through phosphorylation of RNA polymerase II (RNAPII)
.
This activity can be inhibited by THZ1, which is a potent and selective CDK7 covalent inhibitor with a median inhibitory concentration (IC50) of 3.
2 nM
.
THZ1 has been shown to have strong anti-tumor activity against a series of cancers, such as neuroblastoma, small cell lung cancer and triple negative breast cancer
.
The results of this study show that the self-renewal and survival ability of LSC depends to a large extent on the transcription of the gene X-box binding protein 1 (XBP1), which is an oncogene related to SE and is particularly susceptible to SE intervention
.
These findings provide further evidence for the "oncogene addiction" theory and propose potential targeted strategies for the treatment of CML
.
Reference message: https://
