ena-STUDY-MPIMG-15-12-2018-18:47:42:017-113
Modelling the progression from TAM to ML-DS in children with Down syndrome utilizing a murine transplantation model
Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined sequencing data of 252 patients with functional analyses resulting in a novel, multiplex CRISPR-Cas9 screen in an in vivo murine TAM model. We tested loss-of-function mutations of 22 recurrently mutated genes resulting in leukemias that phenotypically, genetically and transcriptionally mirrored ML-DS. This study includes targeted DNA sequencing of 38 different murine leukemia samples, as well as RNA sequencing of six different murine leukemia samples and four different hematopoietic progenitor cell populations derived from FACS sorted murine fetal liver cells (MEP, CMP, GMP, LSK).
Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined sequencing data of 252 patients with functional analyses resulting in a novel, multiplex CRISPR-Cas9 screen in an in vivo murine TAM model. We tested loss-of-function mutations of 22 recurrently mutated genes resulting in leukemias that phenotypically, genetically and transcriptionally mirrored ML-DS. This study includes targeted DNA sequencing of 38 different murine leukemia samples, as well as RNA sequencing of six different murine leukemia samples and four different hematopoietic progenitor cell populations derived from FACS sorted murine fetal liver cells (MEP, CMP, GMP, LSK).