Mechanisms underlying platelet function defect in a pedigree with familial platelet disorder with a predisposition to acute myelogenous leukemia: potential role for candidate RUNX1 targets.

GLEMBOTSKY AC; BLUTEAU D; ESPASANDIN YR; GOETTE NP; MARTA RF; MARIN OYARZUN C; KORIN L; LEV PR; LAGUENZ R; MOLINAS FC; RASLOVA H; HELLER PG

JOURNAL OF THROMBOSIS AND HAEMOSTASIS

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2014 vol. 12 p. 761 - 772

1538-7933

Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/LMA) is an inherited platelet disorder characterized by autosomal dominant thrombocytopenia, platelet function defect and a lifelong risk of development of hematologic neoplasms. Germline heterozygous mutations in transcription factor RUNX1 underlie this disease. Although it still remains a rare condition, this disorder is now being increasingly recognized due to heightened diagnostic awareness and more than forty families have been reported to date. Thrombocytopenia, characterized by normal-sized platelets, is usually mild to moderate and, although present in most patients, low-normal or even normal platelet counts have been reported in some cases. Severity of bleeding varies among affected individuals and tends to be more severe than expected according to the degree of thrombocytopenia, due to the presence of associated platelet function defect. Although the presence of platelet dysfunction seems to be an almost constant feature of this disorder, it is presently unknown whether all individuals with germline RUNX1 mutation display this abnormality. FPD/AML represents a clinically heterogeneous condition. While some affected individuals develop leukemia and have mild or no bleeding diathesis, on the other hand, other patients may present with a predominant platelet function disorder without history of malignancy, as recently described in patients recruited to the UK genotyping and platelet phenotyping (GAPP) study. Likewise, the spectrum and severity of platelet functional abnormalities vary among reported cases. In some patients, the predominant pattern seems to be a platelet secretion defect, while others show a more complex phenotype. The mechanisms by which RUNX1 mutations lead to the platelet function defect remain incompletely understood. Although several studies have revealed the presence of -storage pool disease,Gerrard, Beri, Bujis, Lages, Favier, 5 new pedigrees it is unclear whether this abnormality fully accounts for the platelet phenotype. In this regard, impaired αIIbβ3 integrin activation has been shown in one FPD/LMA patient, providing an alternative explanation for defective platelet function. RUNX1 is a master hematopoietic transcription factor which dimerizes with CBF and is crucial for the establishment of definitive hematopoiesis during embryonic development. Although dispensable for the maintenance of adult hematopoietic stem cells, it plays an essential role in the lymphoid and megakaryocytic lineages, where it is involved in megakaryocyte development, platelet formation and platelet function.