Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1059009 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27381906_1.fastq.gz | Fastqsanger.gz | |||
| SRR27381906_2.fastq.gz | Fastqsanger.gz |
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Project description:Children with Down syndrome have a 150-fold increased risk of developing the myeloid leukemia of Down syndrome (ML-DS). ML-DS is preceded by transient abnormal myelopoiesis (TAM), which spontaneously resolves in most cases but progresses to AML with additional mutations most commonly in the cohesin complex or signaling genes. However, the mechanisms by which these alterations promote leukemia are unknown. Here, we leveraged isogenic cell lines and patient data to investigate the role of cohesin mutations in leukemia progression. Multi-omic analyses revealed that haploinsufficiency of the cohesin complex suppresses the occupancy of CIITA at HLA class II loci, leading to a reduction in HLA Class II gene expression. Surface levels of HLA-DR are lower in ML-DS relative to TAM and these decreased levels are associated with an increased risk of TAM progression. Of note, a decrease in HLA-Class II gene expression is also a feature of non-DS AML with reduced expression of cohesin family members. These data suggest that unlike TAM, ML-DS blasts may evade the immune system by reduced HLA class II expression, providing a new model for leukemia progression in DS.
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Project description:Children with Down syndrome have a 150-fold increased risk of developing the myeloid leukemia of Down syndrome (ML-DS). ML-DS is preceded by transient abnormal myelopoiesis (TAM), which spontaneously resolves in most cases but progresses to AML with additional mutations most commonly in the cohesin complex or signaling genes. However, the mechanisms by which these alterations promote leukemia are unknown. Here, we leveraged isogenic cell lines and patient data to investigate the role of cohesin mutations in leukemia progression. Multi-omic analyses revealed that haploinsufficiency of the cohesin complex suppresses the occupancy of CIITA at HLA class II loci, leading to a reduction in HLA Class II gene expression. Surface levels of HLA-DR are lower in ML-DS relative to TAM and these decreased levels are associated with an increased risk of TAM progression. Of note, a decrease in HLA-Class II gene expression is also a feature of non-DS AML with reduced expression of cohesin family members. These data suggest that unlike TAM, ML-DS blasts may evade the immune system by reduced HLA class II expression, providing a new model for leukemia progression in DS.
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Project description:Children with Down syndrome have a 150-fold increased risk of developing the myeloid leukemia of Down syndrome (ML-DS). ML-DS is preceded by transient abnormal myelopoiesis (TAM), which spontaneously resolves in most cases but progresses to AML with additional mutations most commonly in the cohesin complex or signaling genes. However, the mechanisms by which these alterations promote leukemia are unknown. Here, we leveraged isogenic cell lines and patient data to investigate the role of cohesin mutations in leukemia progression. Multi-omic analyses revealed that haploinsufficiency of the cohesin complex suppresses the occupancy of CIITA at HLA class II loci, leading to a reduction in HLA Class II gene expression. Surface levels of HLA-DR are lower in ML-DS relative to TAM and these decreased levels are associated with an increased risk of TAM progression. Of note, a decrease in HLA-Class II gene expression is also a feature of non-DS AML with reduced expression of cohesin family members. These data suggest that unlike TAM, ML-DS blasts may evade the immune system by reduced HLA class II expression, providing a new model for leukemia progression in DS.
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Project description:Down syndrome (DS) is caused by triplication of Human chromosome 21 (Hsa21) and associated with an array of deleterious phenotypes, including mental retardation, heart defects and immunodeficiency. Genome-wide expression patterns of uncultured peripheral blood cells are useful to understanding of DS-associated immune dysfunction. We used a Human Exon microarray to characterize gene expression in uncultured peripheral blood cells derived from DS individuals and age-matched controls from two age groups: neonate (N) and child (C). A total of 174 transcript clusters (gene-level) with eight located on Hsa21 in N group and 383 transcript clusters including 56 on Hsa21 in C group were significantly dysregulated in DS individuals. Microarray data were validated by quantitative polymerase chain reaction. Functional analysis revealed that the dysregulated genes in DS were significantly enriched in two and six KEGG pathways in N and C group, respectively. These pathways included leukocyte trans-endothelial migration, B cell receptor signaling pathway and primary immunodeficiency, etc., which causally implicated dysfunctional immunity in DS. Our results provided a comprehensive picture of gene expression patterns in DS at the two developmental stages and pointed towards candidate genes and molecular pathways potentially associated with the immune dysfunction in DS.
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Project description:Children with Down syndrome have a 150-fold increased risk of developing the myeloid leukemia of Down syndrome (ML-DS). ML-DS is preceded by transient abnormal myelopoiesis (TAM), which spontaneously resolves in most cases but progresses to AML with additional mutations most commonly in the cohesin complex or signaling genes. However, the mechanisms by which these alterations promote leukemia are unknown. Here, we leveraged isogenic cell lines and patient data to investigate the role of cohesin mutations in leukemia progression. Multi-omic analyses revealed that haploinsufficiency of the cohesin complex suppresses the occupancy of CIITA at HLA class II loci, leading to a reduction in HLA Class II gene expression. Surface levels of HLA-DR are lower in ML-DS relative to TAM and these decreased levels are associated with an increased risk of TAM progression. Of note, a decrease in HLA-Class II gene expression is also a feature of non-DS AML with reduced expression of cohesin family members. These data suggest that unlike TAM, ML-DS blasts may evade the immune system by reduced HLA class II expression, providing a new model for leukemia progression in DS.
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Project description:Children with Down syndrome have a 150-fold increased risk of developing the myeloid leukemia of Down syndrome (ML-DS). ML-DS is preceded by transient abnormal myelopoiesis (TAM), which spontaneously resolves in most cases but progresses to AML with additional mutations most commonly in the cohesin complex or signaling genes. However, the mechanisms by which these alterations promote leukemia are unknown. Here, we leveraged isogenic cell lines and patient data to investigate the role of cohesin mutations in leukemia progression. Multi-omic analyses revealed that haploinsufficiency of the cohesin complex suppresses the occupancy of CIITA at HLA class II loci, leading to a reduction in HLA Class II gene expression. Surface levels of HLA-DR are lower in ML-DS relative to TAM and these decreased levels are associated with an increased risk of TAM progression. Of note, a decrease in HLA-Class II gene expression is also a feature of non-DS AML with reduced expression of cohesin family members. These data suggest that unlike TAM, ML-DS blasts may evade the immune system by reduced HLA class II expression, providing a new model for leukemia progression in DS.
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Project description:Children with Down syndrome have a 150-fold increased risk of developing the myeloid leukemia of Down syndrome (ML-DS). ML-DS is preceded by transient abnormal myelopoiesis (TAM), which spontaneously resolves in most cases but progresses to AML with additional mutations most commonly in the cohesin complex or signaling genes. However, the mechanisms by which these alterations promote leukemia are unknown. Here, we leveraged isogenic cell lines and patient data to investigate the role of cohesin mutations in leukemia progression. Multi-omic analyses revealed that haploinsufficiency of the cohesin complex suppresses the occupancy of CIITA at HLA class II loci, leading to a reduction in HLA Class II gene expression. Surface levels of HLA-DR are lower in ML-DS relative to TAM and these decreased levels are associated with an increased risk of TAM progression. Of note, a decrease in HLA-Class II gene expression is also a feature of non-DS AML with reduced expression of cohesin family members. These data suggest that unlike TAM, ML-DS blasts may evade the immune system by reduced HLA class II expression, providing a new model for leukemia progression in DS.
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