In utero origin of myelofibrosis presenting in adult monozygotic twins
M, N. L.
Simoglou Karali, C.
Clark, S. A.
Wedge, David C
Mead, A. J.
AffiliationMedical Research Council (MRC) Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, National Institute for Health Research Biomedical Research Centre, University of Oxford, Oxford, UK
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AbstractThe latency between acquisition of an initiating somatic driver mutation by a single-cell and clinical presentation with cancer is largely unknown. We describe a remarkable case of monozygotic twins presenting with CALR mutation-positive myeloproliferative neoplasms (MPNs) (aged 37 and 38 years), with a clinical phenotype of primary myelofibrosis. The CALR mutation was absent in T cells and dermal fibroblasts, confirming somatic acquisition. Whole-genome sequencing lineage tracing revealed a common clonal origin of the CALR-mutant MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. Index sorting and single-colony genotyping revealed phenotypic hematopoietic stem cells (HSCs) as the likely MPN-propagating cell. Furthermore, neonatal blood spot analysis confirmed in utero origin of the JAK2V617F mutation in a patient presenting with polycythemia vera (aged 34 years). These findings provide a unique window into the prolonged evolutionary dynamics of MPNs and fitness advantage exerted by MPN-associated driver mutations in HSCs.
CitationSousos N, Ní Leathlobhair M, Simoglou Karali C, Louka E, Bienz N, Royston D, et al. In utero origin of myelofibrosis presenting in adult monozygotic twins. Vol. 28, Nature Medicine. Springer Science and Business Media LLC; 2022. p. 1207–11.
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