Deciphering the Dynamics of Leukemogenic Transformation from Clonal Hematopoiesis in Congenital Neutropenia
Year: 2026
Type: preprint
Abstract: Inherited neutropenia syndromes, severe congenital neutropenia (CN) and Shwachman-Diamond syndrome (SDS), confer a high cumulative risk of MDS and AML. It is not yet clear which somatic mutations, in which combination, allele frequency and sequence identify patients at high risk. We analyzed clonal hematopoiesis (CH) in the largest representative cohort of inherited neutropenia patients to date - 658 samples from 309 patients - using error-corrected panel sequencing with longitudinal sampling. This was complemented in selected cases by single-cell DNA sequencing and genotyping of single-cell derived colonies. CH was detected in early childhood, affecting 37.7% of CN and 60% of SDS patients. The somatic mutation burden remained essentially unchanged over decades. In CN, CSF3R mutations were dominant across genetic subtypes, while additional mutations were rare and included ASXL1, TET2, and DNMT3A. ASXL1 mutations most frequently co-occurred with CSF3R mutations. Co-occurring CSF3R and TP53 mutations were only found in SRP54-CN and CLPB-CN patients. In SDS, TP53 was the most frequently mutated gene, followed by low-prevalence somatic mutations in DNMT3A, IDH1, PTPN11, and RUNX1. In CN-MDS/AML, RUNX1 and SETBP1 mutations emerged shortly before progression to MDS/AML, and membrane-proximal CSF3R mutations only at the leukemic stage. In SDS, biallelic TP53-mutant clones expanded prior to transformation, and a variant allele frequency (VAF) of dominant TP53 clone above 0.074 discriminated between patients who progressed and those who did not. Peripheral blood reflected bone marrow genotype for most key drivers. Leukemic transformation in inherited neutropenia is therefore not stochastic, but rather follows a defined mutational sequence, initiated in childhood.
Authors: Maksim Klimiankou, Sergey Kandabarau, Cornelia Zeidler, Sabine Mellor-Heineke, Maja Haar, Yvonne Lisa Behrens, David C. Dale, Vahagn Makaryan, Merideth Kelley, Audrey Anna Bolyard, Charlotte M. Niemeyer, Miriam Erlacher, Ayami Yoshimi-Noellke, Peter E Newburger, Markus Mezger, Peter Lang, Torsten Haferlach, Niroshan Nadarajah, Claudia Lengerke, Karl Welte, Julia Skokowa
Institutions: STZ eyetrial, University of Tübingen, Medizinische Hochschule Hannover, University of Washington, University of Freiburg, University Medical Center Freiburg, Universität Ulm, University Hospital Ulm, University of Massachusetts Chan Medical School, University Children's Hospital Tübingen, Munich Leukemia Laboratory (Germany)
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225800261
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