Longitudinal sequencing of RUNX1 familial platelet disorder: new insights into genetic mechanisms of transformation to myeloid malignancies.
Bruno Kosa L DuarteGabriela G Yamaguti-HayakawaSamuel S MedinaLúcia H SiqueiraBrooke SnetsingerFernando F CostaMichael J RauhMargareth Castro OzeloPublished in: British journal of haematology (2019)
The mechanisms by which patients with RUNX1 familial platelet disorder with propensity to myeloid malignancies (FPDMM) develop myeloid malignancies (MM) are not fully understood. We report the results of targeted next-generation sequencing on three patients with RUNX1 FPDMM who developed acute myeloid leukaemia or myelodysplastic syndromes (AML/MDS). DNA samples were collected from bone marrow, peripheral blood and buccal swabs at different time points. One patient had clonal haematopoiesis, represented by an SRSF2 p.P95R variant, prior to his AML diagnosis, when he developed an additional NRAS p.G12D variant. His sister presented to us with MDS, with a TET2 p.S471fs and identical NRAS p.G12D variant. The third patient, from another family, had an additional RUNX1 p.R204X and an NFE2 p.Q139fs variant at AML diagnosis. This constitutes the first report of NFE2 variants in AML without extramedullary disease and NRAS variants in AML/MDS in the setting of FPDMM. A systematic review of the literature including our findings distinguishes two genetic landscapes at AML transformation from FPDMM characterized by either the presence or absence of somatic abnormalities in RUNX1 with or without variants in genes usually associated with MM. Whether clonal haematopoiesis precedes transformation only in patients without somatic abnormalities in RUNX1 needs further confirmation.
Keyphrases
- acute myeloid leukemia
- copy number
- bone marrow
- transcription factor
- allogeneic hematopoietic stem cell transplantation
- genome wide
- peripheral blood
- dendritic cells
- end stage renal disease
- case report
- circulating tumor
- dna methylation
- ejection fraction
- mesenchymal stem cells
- chronic kidney disease
- immune response
- wild type
- prognostic factors
- intensive care unit
- respiratory failure
- peritoneal dialysis
- genome wide identification