Deciphering the role of KANSL1 mutations in the development of Myeloid Leukemia in children with Down Syndrome (ML-DS)

Transient abnormal myelopoiesis (TAM) is a form of clonal hematopoiesis seen in infants with trisomy 21. TAM is caused by mutations in the transcription factor GATA1, leading to the expression of a shortened isoform (GATA1s). TAM clonally evolves at high percentage to myeloid leukemia in Down syndrome (ML-DS) upon acquisition of secondary mutations. Leveraging a virus-free CRISPR platform to introduce GATA1s and additional mutations in primary human fetal liver hematopoietic stem and progenitor cells (hFL-HSPCs) followed by in vitro testing and in vivo xenotransplantation assays, we revealed KANSL1 loss to be a potent oncogenic event driving progression from clonal hematopoiesis to frank leukemia. To define the role of KANSL1 mutations in normal and malignant hematopoiesis, we are performing loss-of-function assays to investigate KANSL1 essentiality. Furthermore, we are establishing dTAG degron knock-in cell lines for proteomic, transcriptomic and epigenomic assays in order to define the KANSL1 interactome in leukemic cells. Future research will explore potential new therapeutic vulnerabilities in ML-DS patients carrying mutated KANSL1.