Longitudinal sequencing of RUNX 1 familial platelet disorder: new insights into genetic mechanisms of transformation to myeloid malignancies

Summary The mechanisms by which patients with RUNX 1 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 RUNX 1 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 SRSF 2 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 TET 2 p.S471fs and identical NRAS p.G12D variant. The third patient, from another family, had an additional RUNX 1 p.R204X and an NFE 2 p.Q139fs variant at AML diagnosis. This constitutes the first report of NFE 2 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 RUNX 1 with or without variants in genes usually associated with MM . Whether clonal haematopoiesis precedes transformation only in patients without somatic abnormalities in RUNX 1 needs further confirmation.