1. In utero origin of myelofibrosis presenting in adult monozygotic twins
- Author
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Sousos, N, Ní Leathlobhair, M, Simoglou Karali, C, Louka, E, Bienz, N, Royston, D, Clark, S-A, Hamblin, A, Howard, K, Mathews, V, George, B, Roy, A, Psaila, B, Wedge, DC, and Mead, AJ
- Subjects
Myeloproliferative Disorders ,Primary Myelofibrosis ,Mutation ,Humans ,Twins, Monozygotic ,General Medicine ,Janus Kinase 2 ,Calreticulin ,General Biochemistry, Genetics and Molecular Biology - Abstract
The 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.
- Published
- 2022