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Modeling Down syndrome AML by introducing disese-specific mutations in iPSCs

ABSTRACT: Down syndrome AML is characterized by the presence of the pathgnonomic mutation in GATA1, which cooperates with other somatic mutations. In this study, we utilzed iPSCs derived from Down syndrome individuals bearing trisomy 21 and introduced disease-specific mutations using CRISPR-Cas9. Hematopoeitic stem and progenitor cells (HSPCs) obtained by hematopoeitic differentiation of these iPSCs, and megakaryocytes generated from the HSPCs (by culturing in megakaryocyte-specific media) were used for RNA sequencing analysis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188568 | GEO | 2022/03/02

REPOSITORIES: GEO

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Modeling Down syndrome AML by introducing disese-specific mutations in iPSCs

Project description:Modeling Down syndrome AML by introducing disese-specific mutations in iPSCs

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Project description:Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contribute to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects. mRNA-seq profiling of iPS cells (4 euploid and 3 trisomy 21) derived from fibroblasts of monozygotic twins discordant for trisomy 21

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