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In recent years, with the improvement of treatment methods, the 5-year survival rate of children with acute lymphoblastic leukemia (ALL) has increased to more than 90%
.
However, due to the recurrence of some patients after chemotherapy resistance, ALL is still one of the main cancer types leading to death in children
.
The introduction of multi-omics methods based on genomics has continuously revealed the transcription factors and epigenetic regulatory gene mutations closely related to childhood ALL
.
Recent studies have found that mutations in CREBBP, FPGS, MSH2, NR3C1, NT5C2, PRPS1, TP53, and NSD2 are particularly associated with the recurrence of childhood ALL
.
Among them, NSD2 is significantly related to the early recurrence of childhood ALL, suggesting that its mutation may be involved in the resistance of ALL chemotherapeutics and cause disease recurrence
.
NSD2 (MMSET/WHSC1) belongs to a family of nuclear receptor binding SET domain proteins (NSD1, NSD2 and NSD3)
.
The histone methyltransferase encoded by it catalyzes the transfer of methyl groups to the 36th lysine (H3K36) at the end of histone H3, and specifically catalyzes the dimethylation modification of H3K36, thus maintaining chromatin stability and regulating gene expression.
Has an important role
.
Previous studies on NSD2 mainly focused on t(4;14) multiple myeloma (MM), so it is also called MMSET
.
NSD2 is highly expressed in t(4;14) multiple myeloma, causing an increase in H3K36me2 and a decrease in H3K27m3, resulting in abnormal gene expression
.
Unlike multiple myeloma, NSD2 is mainly genetic mutations in acute lymphocytic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma, not increased expression
.
Among them, the mutation of glutamic acid at position 1009 in the SET domain in childhood acute lymphoblastic leukemia to lysine (E1099K) is the most common
.
This mutation also causes the overall increase of H3K36me2 and the decrease of H3K27me3 in the cells, leading to abnormal gene expression, promoting the proliferation, adhesion and migration of leukemia cells and the invasion of the central nervous system
.
However, how mutations in the NSD2 gene cause ALL recurrence has been confusing
.
Recently, the Jonathan Licht team of the Department of Hematology Oncology, University of Florida Cancer Research Center, in collaboration with the Australian Institute of Childhood Oncology and the National Institutes of Health, with Dr.
Jianping Li as the first author, published the title PRC2 Inhibitors Overcome Glucocorticoid Resistance in Cancer Discovery.
Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia" research results
.
Researchers use CRISPR/Cas9 to edit ALL cell lines, NOD SCID, and leukemia patient-derived xenograft tumors (PDX) and other models, applying a large number of drug screening and appearance Multi-omics analysis of genetic regulation revealed a new mechanism of glucocorticoid resistance in children with acute lymphoblastic leukemia with NSD2 gene mutations, and found a new strategy for reversing glucocorticoid resistance based on this
.
Based on the close relationship between NSD2 mutation and ALL recurrence, the researchers first screened tens of thousands of drugs on ALL cell lines edited by CRISPR/Cas9
.
Although no specific targeted drugs for NSD2 mutations have been found, the researchers were surprised to find that ALL cell lines with NSD2 mutations are specifically resistant to glucocorticoids and not resistant to other ALL chemotherapeutics
.
After knocking out the p.
E1099K mutation site by CRISPR/Cas9 and reversing it to wild-type NSD2, ALL cell lines (RCH-ACV, SEM and RPMI-8402) began to be sensitive to glucocorticoids (dexamethasone); in wild-type NSD2 The p.
E1099K mutation site was transferred into the ALL cell line (CEM), and the leukemia cell line is resistant to glucocorticoids
.
In vivo transplantation experiments of PDX cells and CRISPR/Cas9-edited ALL cell lines in NOD SCID mice further confirmed this finding
.
Subsequently, the researchers tried to elucidate the mechanism of glucocorticoid resistance in NSD2 mutant ALL cells through epigenetic multi-omics methods
.
Different from the gene expression profile of glucocorticoid-sensitive NSD2 wild-type ALL cells, NSD2 mutant cells have chromatin accessibility to glucocorticoid therapy, transcriptional response, and glucocorticoid receptor (GR) binding to target gene DNA The ability of NSD2 is significantly inhibited; the main reason is that the NSD2 mutation prevents the expression of the NR3C1 gene encoding the glucocorticoid receptor and self-activation, making it unable to respond to glucocorticoid treatment
.
The researchers found through chromatin immunoprecipitation ChIP-Seq that although the overall level of H3K27me3 is reduced in NSD2 mutant ALL, it is significantly enriched in the promoter region of the NR3C1 gene encoding the glucocorticoid receptor, thereby inhibiting the NR3C1 gene.
Transcription expression and self-activation
.
The low levels of glucocorticoid receptors in NSD2 mutant ALL cells are not sufficient to respond to dexamethasone treatment, nor can they further regulate the expression and induction of downstream target genes (such as BCL2L11, BMF, NFKBIA, etc.
) through GR, CTCF and H3K27ac Apoptosis eventually leads to ineffective glucocorticoid therapy
.
Overexpression of glucocorticoids in NSD2 mutant ALL cells restores their sensitivity and induces apoptosis
.
Based on this finding, the researchers tried to apply different PRC2 (polycomb repressive complex 2) inhibitors to pretreat the NSD2 mutant ALL cell line to reduce the enrichment of H3K27me3 in the NR3C1 gene promoter region, and then proceed with glucocorticoid therapy
.
The results of in vitro experiments and PDX in vivo experiments showed that this strategy significantly reversed the glucocorticoid resistance of NSD2 mutant ALL cells (B-ALL and T-ALL)
.
PRC2 inhibitors, mainly EZH2, re-induced the transcription and activation of NR3C1, and restored the level of glucocorticoid receptor; thus combined with glucocorticoid to induce downstream pro-apoptotic gene expression to achieve the purpose of treatment
.
As one of the key drugs in chemotherapy regimens for ALL patients, glucocorticoids can induce ALL cell apoptosis through a variety of ways
.
The early resistance of glucocorticoids is obviously related to the prognosis of ALL.
Taking effective intervention measures to restore its sensitivity will improve the recurrence and long-term survival rate of ALL patients
.
The study started with mutations in the NSD2 gene associated with ALL recurrence, and through a large number of drug screenings combined with large-scale omics sequencing technology, it revealed a new mechanism of epigenetic regulation that leads to glucocorticoid resistance, and proposed effective methods based on this.
Targeted therapy provides new ideas and basis for glucocorticoid resistance in ALL patients
.
Original link: https://cancerdiscovery.
aacrjournals.
org/content/early/2021/08/20/2159-8290.
CD-20-1771 Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article , Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated
.
.
However, due to the recurrence of some patients after chemotherapy resistance, ALL is still one of the main cancer types leading to death in children
.
The introduction of multi-omics methods based on genomics has continuously revealed the transcription factors and epigenetic regulatory gene mutations closely related to childhood ALL
.
Recent studies have found that mutations in CREBBP, FPGS, MSH2, NR3C1, NT5C2, PRPS1, TP53, and NSD2 are particularly associated with the recurrence of childhood ALL
.
Among them, NSD2 is significantly related to the early recurrence of childhood ALL, suggesting that its mutation may be involved in the resistance of ALL chemotherapeutics and cause disease recurrence
.
NSD2 (MMSET/WHSC1) belongs to a family of nuclear receptor binding SET domain proteins (NSD1, NSD2 and NSD3)
.
The histone methyltransferase encoded by it catalyzes the transfer of methyl groups to the 36th lysine (H3K36) at the end of histone H3, and specifically catalyzes the dimethylation modification of H3K36, thus maintaining chromatin stability and regulating gene expression.
Has an important role
.
Previous studies on NSD2 mainly focused on t(4;14) multiple myeloma (MM), so it is also called MMSET
.
NSD2 is highly expressed in t(4;14) multiple myeloma, causing an increase in H3K36me2 and a decrease in H3K27m3, resulting in abnormal gene expression
.
Unlike multiple myeloma, NSD2 is mainly genetic mutations in acute lymphocytic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma, not increased expression
.
Among them, the mutation of glutamic acid at position 1009 in the SET domain in childhood acute lymphoblastic leukemia to lysine (E1099K) is the most common
.
This mutation also causes the overall increase of H3K36me2 and the decrease of H3K27me3 in the cells, leading to abnormal gene expression, promoting the proliferation, adhesion and migration of leukemia cells and the invasion of the central nervous system
.
However, how mutations in the NSD2 gene cause ALL recurrence has been confusing
.
Recently, the Jonathan Licht team of the Department of Hematology Oncology, University of Florida Cancer Research Center, in collaboration with the Australian Institute of Childhood Oncology and the National Institutes of Health, with Dr.
Jianping Li as the first author, published the title PRC2 Inhibitors Overcome Glucocorticoid Resistance in Cancer Discovery.
Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia" research results
.
Researchers use CRISPR/Cas9 to edit ALL cell lines, NOD SCID, and leukemia patient-derived xenograft tumors (PDX) and other models, applying a large number of drug screening and appearance Multi-omics analysis of genetic regulation revealed a new mechanism of glucocorticoid resistance in children with acute lymphoblastic leukemia with NSD2 gene mutations, and found a new strategy for reversing glucocorticoid resistance based on this
.
Based on the close relationship between NSD2 mutation and ALL recurrence, the researchers first screened tens of thousands of drugs on ALL cell lines edited by CRISPR/Cas9
.
Although no specific targeted drugs for NSD2 mutations have been found, the researchers were surprised to find that ALL cell lines with NSD2 mutations are specifically resistant to glucocorticoids and not resistant to other ALL chemotherapeutics
.
After knocking out the p.
E1099K mutation site by CRISPR/Cas9 and reversing it to wild-type NSD2, ALL cell lines (RCH-ACV, SEM and RPMI-8402) began to be sensitive to glucocorticoids (dexamethasone); in wild-type NSD2 The p.
E1099K mutation site was transferred into the ALL cell line (CEM), and the leukemia cell line is resistant to glucocorticoids
.
In vivo transplantation experiments of PDX cells and CRISPR/Cas9-edited ALL cell lines in NOD SCID mice further confirmed this finding
.
Subsequently, the researchers tried to elucidate the mechanism of glucocorticoid resistance in NSD2 mutant ALL cells through epigenetic multi-omics methods
.
Different from the gene expression profile of glucocorticoid-sensitive NSD2 wild-type ALL cells, NSD2 mutant cells have chromatin accessibility to glucocorticoid therapy, transcriptional response, and glucocorticoid receptor (GR) binding to target gene DNA The ability of NSD2 is significantly inhibited; the main reason is that the NSD2 mutation prevents the expression of the NR3C1 gene encoding the glucocorticoid receptor and self-activation, making it unable to respond to glucocorticoid treatment
.
The researchers found through chromatin immunoprecipitation ChIP-Seq that although the overall level of H3K27me3 is reduced in NSD2 mutant ALL, it is significantly enriched in the promoter region of the NR3C1 gene encoding the glucocorticoid receptor, thereby inhibiting the NR3C1 gene.
Transcription expression and self-activation
.
The low levels of glucocorticoid receptors in NSD2 mutant ALL cells are not sufficient to respond to dexamethasone treatment, nor can they further regulate the expression and induction of downstream target genes (such as BCL2L11, BMF, NFKBIA, etc.
) through GR, CTCF and H3K27ac Apoptosis eventually leads to ineffective glucocorticoid therapy
.
Overexpression of glucocorticoids in NSD2 mutant ALL cells restores their sensitivity and induces apoptosis
.
Based on this finding, the researchers tried to apply different PRC2 (polycomb repressive complex 2) inhibitors to pretreat the NSD2 mutant ALL cell line to reduce the enrichment of H3K27me3 in the NR3C1 gene promoter region, and then proceed with glucocorticoid therapy
.
The results of in vitro experiments and PDX in vivo experiments showed that this strategy significantly reversed the glucocorticoid resistance of NSD2 mutant ALL cells (B-ALL and T-ALL)
.
PRC2 inhibitors, mainly EZH2, re-induced the transcription and activation of NR3C1, and restored the level of glucocorticoid receptor; thus combined with glucocorticoid to induce downstream pro-apoptotic gene expression to achieve the purpose of treatment
.
As one of the key drugs in chemotherapy regimens for ALL patients, glucocorticoids can induce ALL cell apoptosis through a variety of ways
.
The early resistance of glucocorticoids is obviously related to the prognosis of ALL.
Taking effective intervention measures to restore its sensitivity will improve the recurrence and long-term survival rate of ALL patients
.
The study started with mutations in the NSD2 gene associated with ALL recurrence, and through a large number of drug screenings combined with large-scale omics sequencing technology, it revealed a new mechanism of epigenetic regulation that leads to glucocorticoid resistance, and proposed effective methods based on this.
Targeted therapy provides new ideas and basis for glucocorticoid resistance in ALL patients
.
Original link: https://cancerdiscovery.
aacrjournals.
org/content/early/2021/08/20/2159-8290.
CD-20-1771 Plate maker: Notes for reprinting on the 11th [Non-original article] The copyright of this article belongs to the author of the article , Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated
.
