Co-Occurring CSF3R W791* Germline and Somatic T618I Driver Mutations Induce Early CNL and Clonal Progression to Mixed Phenotype Acute Leukemia.

Chronic neutrophilic leukemia (CNL) relates to mutational CSF3R activation with membrane proximal mutations such as T618I as driver mutations, but the significance of truncating 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-occurring germline and somatic 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 follicle. To investigate a potential predisposition for CNL development and progression by germline -W791*, allelic localizations were evaluated. We detected a somatic -T618I mutation at 46% variant allele frequency (VAF) at the time of CNL diagnosis, which co-occurred with a -W791* truncation at 50% VAF in the germline. Evaluation of allelic localization revealed -T618I and W791* on the same allele. A concomitant 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 double-mutant clone to 90% VAF via copy neutral loss of heterozygosity on chromosome 1p and the emergence of a 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 -W791* mutation in the germline and acquisition of -T618I on the same allele compatible with increased susceptibility for mutation acquisition facilitating -related clonal transformation.