Familial platelet disorder with predisposition to acute myelogenous leukemia.

HELLER PG; GLEMBOTSKY AC.

Atlas of Genetics and Cytogenetics in Oncology and Haematology

University Hospital of Poitiers

Año: 2012; p. 138 - 143

Inheritance Familial platelet disorder with predisposition to acute myelogenous leukemia (FPD/AML) is an autosomal dominant disorder caused by germline heterozygous mutations in the hematopoietic transcription factor RUNX1. Thirty-six pedigrees have been reported to date. Although rare, the frequency of this disorder has been probably underestimated and it is now being increasingly recognized due to enhanced awareness. FPD/AML represents one of the few identified genetic disorders underlying pure familial myelodysplastic syndrome (MDS)/AML cases and represents a useful model to unravel the role of RUNX1 in leukemogenesis. Clinics FPD/AML is characterized by inherited thrombocytopenia, platelet function defect and a lifelong risk of development of hematologic malignancies (Song et al, 1999). Thrombocytopenia is usually mild to moderate and is characterized by normal platelet size. Bleeding tends to be more severe than expected according to the degree of thrombocytopenia due to the presence of associated platelet dysfunction and may result in a significant bleeding diathesis. Platelet aggregation is abnormal in response to several platelet agonists and an aspirin-like defect has been described. Although thrombocytopenia is almost always present, normal or low-normal platelet counts have been reported in some patients. Similarly, although platelet dysfunction represents a very frequent feature of this disorder, at present, it is unknown whether all individuals with germline RUNX1 mutation display this abnormality. Furthermore, as platelet function tests are not always routinely performed, the platelet defect may be overlooked in patients with mild bleeding manifestations, leading to failure to identify affected individuals. Recently, decreased megakaryocyte maturation and polyploidization and impaired proplatelet formation have been found to underlie the defect in platelet production (Bluteau et al, 2012), while platelet dysfunction has been attributed to both platelet storage pool deficiency (Gerard et al, 1991) and impaired IIb3 integrin activation (Sun et al, 2004). Several RUNX1-targets have been proposed to be responsible for the platelet defects, including the Mpl receptor (Heller et al, 2005), myosins 9 and 10 (Bluteau et al, 2012), myosin regulatory light chain 9 (Sun et al, 2007), arachidonate 12-lipoxygenase and PKC (Sun et al, 2004), although other genes are probably involved.