IN VITRO MODEL OF STAGE-SPECIFIC EVOLUTION OF CLONAL HEMATOPOIESIS IN CN TO CN/AML

Background and Aims: Severe congenital neutropenia (CN) is a rare inherited bone marrow failure syndrome caused by mutations in ELANE and HAX1, among others. Despite improved survival with G-CSF therapy, CN remains a pre-leukemic condition, with >20% of patients progressing to MDS/AML. CN leukemic transformation follows a stepwise acquisition of somatic mutations, beginning with CSF3R, followed by RUNX1, ASXL1, and SETBP1. We aimed to establish an in vitro model that recapitulates this process and to identify key molecular drivers CN leukemogenesis.