Activating CSF2RB mutations contribute to TAM/ML-DS transformation

Introduction: AML in children with Down syndrome (ML-DS) evolves from transient abnormal myelopoiesis (TAM) by acquisition of unknown genetic lesions. Exome sequencing identified prevalent mutations in the IL3-, IL5-, CSF2-receptor common chain CSF2RB (CSF2RBmut) as a potential oncogenic driver. Methods: The role of CSF2RBmut in ML-DS transformation was explored by lentiviral expression in cell lines and human hematopoietic stem and progenitor cells (HSPCs) followed by growth competition assays, kinase signaling analyses, and directed differentiation. Results: Ectopic expression of CSF2RBmut facilitated cytokine…