GENETIC ORIGINS AND CLONAL TRAJECTORIES OF MONOSOMY 7 IN PEDIATRIC MDS

Background and Aims: Classical myeloproliferative neoplasms (MPN) including the phenotypes essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) are usually diagnosed in older adulthood and only exceptionally in childhood and adolescence.Retrospective analyses suggest that a considerable proportion of pediatric patients develop serious complications conveying a need for systematic prospective analyses.Methods: Clinical and hematological data of pediatric patients prospectively diagnosed with classical MPN and enrolled in the German national MPN Childhood Registry was evaluated.In addition, deep targeted sequencing including 148 leukemia-associated genes / gene regions and deep whole exome sequencing (WES) were performed in all cases.Results:Between January 2023 and March 2025, n=34 pediatric patients newly diagnosed with either ET (n=28) or PV (n=6) were enrolled in the German MPN Childhood Registry.Median age at diagnosis was 14.5 years.Twenty-two patients (65%) were female and 12 (35%) were male.Eighteen patients (53%) were symptomatic at diagnosis, mostly associated with pronounced pain, and less frequently also bleeding and thrombosis.Splenomegaly was present in 16 cases (47%).Median platelet count in patients with ET was 1.200 G/L.Eighteen patients (53%) carried a JAK2V617F mutation, five (15%) had a mutation in CALR, and nine individuals (26%) were triple-negative for the classical driver mutations in JAK2, CALR, and MPL.The JAK2V617F mutation was clearly associated with splenomegaly whereas no splenomegaly was observed in the triple-negative group.Some additional pathogenic variants were identified especially in genes associated with the DNA damage response.Conclusions: This preliminary analysis underscores the clinical and scientific importance of continuous data acquisition on pediatric patients with MPN.Further genetic analyses with a focus on novel pathogenic somatic variants in triple-negative patients and pathogenic germline variants predisposing to the early onset of the disease will enhance our understanding of the pathogenesis of MPN in these age groups.