Transcription factor defects causing platelet disorders

Abstract

Recent years have seen increasing recognition of a subgroup of inherited platelet function disorders which are due to defects in transcription factors that are required to regulate megakaryopoiesis and platelet production. Thus, germline mutations in the genes encoding the haematopoietic transcription factors RUNX1, GATA-1, FLI1, GFI1b and ETV6 have been associated with both quantitative and qualitative platelet abnormalities, and variable bleeding symptoms in the affected patients. Some of the transcription factor defects are also associated with an increased predisposition to haematologic malignancies (RUNX1, ETV6), abnormal erythropoiesis (GATA-1, GFI1b, ETV6) and immune dysfunction (FLI1). The persistence of MYH10 expression in platelets is a surrogate marker for FLI1 and RUNX1 defects. Characterisation of the transcription factor defects that give rise to platelet function disorders, and of the genes that are differentially regulated as a result, are yielding insights into the roles of these genes in platelet formation and function.

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders

“…These variants are expected to affect the function of RUNX1, as 2 (p.Gln268* and p.Asn159Ser) lie within the RUNT homology domain which mediates DNA binding and heterodimerization with CBFβ and the remaining (p.Ser402Phe) in the C-terminal inhibitory domain of RUNX1 . 37 Comprehensive interpretation of variants in this transcription factor, like those in ANKRD26 (Case 72 in our series), is relevant as such variants may increase the risk of developing myeloid malignancies. 37 , 38 …”

“… 37 Comprehensive interpretation of variants in this transcription factor, like those in ANKRD26 (Case 72 in our series), is relevant as such variants may increase the risk of developing myeloid malignancies. 37 , 38 …”

Clonal hematopoietic mutations linked to platelet traits and the risk of thrombosis or bleeding

“…Mutations in genes encoding for these transcription factors, along with epigenetic regulators, are accompanied with quantitative and/or qualitative platelet abnormalities, causing thrombo-hemorrhagic complications. 4 Multiple growth factors control megakaryopoiesis and platelet production, of which thrombopoietin and its binding to the thrombopoietin receptor plays a primary role. 5 Megakaryocytes undergo endomitosis to become polyploid and during maturation extensive reorganization of cytoskeletal proteins is required for proplatelet formation and the budding of platelets.…”

Genetic Techniques Used in the Diagnosis of Inherited Platelet Disorders

“…Moreover, there is an 40% risk of developing myeloid malignancy. 2 Detecting some types of IPD may inform selection of specific treatments, such as the use of thrombopoietin receptor agonists to temporarily correct thrombocytopenia in MYH9-related disorder (MYH9-RD) 3,4 and DIAPH1-related disorder. 5 Moreover, correctly distinguishing heritable thrombocytopenia from immune thrombocytopenia reduces the likelihood of ineffective and potentially dangerous therapies such as corticosteroids, intravenous immunoglobulins, and splenectomy.…”