Work

In Vitro Model of Stage-specific Evolution of Clonal Hematopoiesis in Cn to Cn/aml

Year: 2025

Type: article

Abstract: Background and Aims: Severe congenital neutropenia (CN) is a bone marrow failure syndrome associated with a high cumulative risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).CSF3R mutations are the main drivers of clonal hematopoiesis (CH) in CN patients.In this study we aimed to characterize the acquisition of somatic mutations additional to CSF3R using an extended gene panel in the large and representative cohort of CN patients.Methods: Error-corrected sequencing on panel of genes and "hotspot" regions recurrently mutated in MDS/AML.Results: We analyzed 222 CN patients at the neutropenia stage, 35 CN patients who developed MDS/AML, 20 cord blood samples, and 20 healthy donors.CH in leukemia-free samples was detected in 36% of CN cases.Mutations in CSF3R were the most common somatic alterations in CN patients, irrespective of genetic subtype.Additional somatic alterations were infrequent and widely scattered.Mutations in ASXL1 (n=8) were the second most frequent somatic event followed by TP53 (n=4), and TET2 (n=4).CN patients with more than one mutated gene in pre-leukemic phase had higher probability to progress to AML/MDS (Fisher's exact test (FAT); OR 7.6; 95% CI, 2.7 -21.5, p=4.22 × 10 -5 ).Enrichment of CSF3R (FAT, OR 7.8; 95% CI, 2.7 -25.6, p=1.34 × 10 -5 ) and RUNX1 (FAT, OR 11; 95% CI, 0.76 -158.9, p=0.04)mutations was identified in CN patients who progressed to MDS/AML when compared to leukemiafree CN cohort.CH in CN patients was detected already in early age but didn't increase over time, diverging from the age-related pattern seen in "classical" CH.In CN-MDS/AML samples we identified prevalence of CSF3R (63%), RUNX1 (41%), ASXL1 (22%), PTPN11 (15%), and SETBP1 (15%) mutations.Conclusions: Although additional somatic mutations were rare, their detection during molecular surveillance was critical, as they correlated with an increased risk of leukemic progression in CN patients.

Source: EJC Paediatric Oncology

DOI: 10.1016/j.ejcped.2025.100340

Authors: Natalia Borbaran Bravo, Anna-Sophia Hellmuth, Sergey Kandabarau, Maksim Klimiankou, Julia Skokowa

Institutions: Universitätsklinikum Tübingen, University of Tübingen

Language: English

Topic: Blood disorders and treatments

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,340