Chronic neutrophilic leukemia (CNL) relates to mutational CSF3R activation with mem-brane proximal CSF3R mutations such as T618I as driver mutations, but the significance of truncat-ing mutations is not clarified. In CNL, concomitant mutations promote disease progression, but insight into longitudinal acquisition is incomplete. In this study, we investigated the role of co-oc-curring germline and somatic CSF3R mutations in CNL, and assessed the impact of clonal evolution on transformation to acute leukemia. We employed sequential next generation sequencing and SNP array karyotyping to assess clonal evolution in CNL of early manifestation age based on a 33-year-old patient. Germline vs. somatic mutations were differentiated using a sample from the hair folli-cle. To investigate a potential predisposition for CNL development and progression by germline CSF3R-W791*, allelic localizations were evaluated. We detected a somatic CSF3R-T618I mutation at 46% variant allele frequency (VAF) at the time of CNL diagnosis, which co-occurred with a CSF3R-W791* truncation at 50% VAF in the germline. Evaluation of allelic localization revealed CSF3R-T618I and W791* on the same allele. A concomitant ASXL1 mutation at 39% VAF increased to 48% VAF upon transformation to mixed phenotype acute leukemia (MPAL), which has both myeloid and lymphoid features. Clonal evolution further involved expansion of the CSF3R double-mutant clone to 90% VAF via copy neutral loss of heterozygosity on chromosome 1p and the emergence of a RUNX1 mutant subclone. Allogeneic transplantation induced complete remission. This study highlights that CNL not only transforms to AML but also to MPAL. The molecular evolution is especially interesting with a CSF3R-W791* mutation in the germline and acquisition of CSF3R-T618I on the same allele compatible with increased susceptibility for mutation acquisition facilitating RUNX1-related clonal transformation.
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Funding: This work was generously supported by research grants from Swiss National Science Foundation (PCEFP3_181357), the Swiss BRIDGE Foundation (PSB-4066-06-2016), the Cancer League Basel and the “Stiftung für krebskranke Kinder Regio Basiliensis” (KLbB-4784-02-2019) and the Foundation for the Fight against Cancer to SCM. JEM is supported by NIH/NHLBI R01 HL157147-01 and a Concern Foundation Conquer Cancer Now Award.
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