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Mapping the Cellular Origin and Early Evolution of Down Syndrome Leukemogenesis [miRNA-Seq]

ABSTRACT: Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia. As Down syndrome leukemogenesis initiates during fetal development, we sought to characterize the cellular mechanisms of preleukemic initiation and leukemic progression using CRISPR/Cas9-mediated gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. Compared to disomic fetal liver, trisomy 21 initiated atypical fetal hematopoiesis, in part through up-regulation of chromosome 21 miRNAs. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells. By contrast, progression to leukemia was independent of trisomy 21 and originated in a wide spectrum of stem and progenitor cells through additional mutations in cohesin genes such as STAG2. CD117+ cells mediated the propagation and progression of the preleukemic and leukemic disease. Treatment with small molecule CD117/KIT inhibitors efficiently targeted preleukemic stem cells and blocked progression to leukemia; thereby laying the groundwork for early prevention strategies in Down syndrome newborns.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160095 | GEO | 2021/07/08

REPOSITORIES: GEO

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Mapping the Cellular Origin and Early Evolution of Down Syndrome Leukemogenesis [CUT&RUN]

Project description:Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia. As Down syndrome leukemogenesis initiates during fetal development, we sought to characterize the cellular mechanisms of preleukemic initiation and leukemic progression using CRISPR/Cas9-mediated gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. Compared to disomic fetal liver, trisomy 21 initiated atypical fetal hematopoiesis, in part through up-regulation of chromosome 21 miRNAs. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells. By contrast, progression to leukemia was independent of trisomy 21 and originated in a wide spectrum of stem and progenitor cells through additional mutations in cohesin genes such as STAG2. CD117+ cells mediated the propagation and progression of the preleukemic and leukemic disease. Treatment with small molecule CD117/KIT inhibitors efficiently targeted preleukemic stem cells and blocked progression to leukemia; thereby laying the groundwork for early prevention strategies in Down syndrome newborns.

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