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 children with trisomy 21. TAM is caused by mutations in the transcription factor GATA1, leading to the expression of a shortened isoform (GATA1s). TAM clonally progresses to myeloid leukemia in Down syndrome (ML-DS) upon acquisition of secondary mutations. Leveraging a virus-free CRISPR screening platform, GATA1s and additional mutations were introduced into primary human fetal liver hematopoietic stem and progenitor cells (hFL-HSPCs). In vitro testing and in vivo xenotransplantation assays revealed KANSL1 mutations to be a potent oncogenic driver of the progression from TAM to fully developed leukemia. To characterize the role of KANSL1 mutations, we performed loss-of-function assays. We revealed domains of KANSL1 essential for normal hematopoiesis and leukemic growth. Moreover, we aim to describe KANSL1 interactome to gain insight into its contribution to the epigenome and gene expression. This knowledge will help us further define the impact of mutated KANSL1 on downstream pathways. Future research will explore potential new therapeutic vulnerabilities in ML-DS patients carrying mutated KANSL1.

Publikationsverlauf

Artikel online veröffentlicht:
10. Mai 2024