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.
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.