Paris-Trousseau: evidence keeps pointing to FLI1

In this issue of Blood, Stevenson et al describe a family with a homozygous missense mutation in FLI1 that is associated with a platelet phenotype identical to the one observed in Paris-Trousseau syndrome, supporting existing evidence that FLI1 is directly involved in the mechanism of thrombocytopenia observed in this disease.¹ 

Patients with a terminal deletion of the long arm of chromosome 11 exhibit several developmental abnormalities and distinctive facial features. This rare disorder is known as Jacobsen syndrome. A large majority of these individuals (>90%) have a bleeding diathesis called Paris-Trousseau thrombocytopenia characterized by autosomal dominant thrombocytopenia and a subpopulation of platelets that exhibit abnormal responses to thrombin and contain giant α-granules.²  The thrombocytopenia can be severe but often resolves during adolescence. The bleeding phenotype is variable with reports of excessive bleeding even after normalization of the platelet counts, indicating an intrinsic platelet defect.³  One of the characteristic findings in the bone marrow of patients with this disorder is the presence of 2 populations of megakaryocytes: 1 population of normal appearing megakaryocytes and the other one represented by micromegakaryocytes.

The 11q deletions can span up to 16 megabases and 300 genes with several of them being potential candidates for the platelet phenotype. Among these, FLI1 (a member of the ETS [E-twenty-six] family of transcription factors), is a natural candidate because it has been identified as a key regulator of megakaryopoiesis and its hemizygous deficiency has been previously associated with defective megakaryocyte development in a murine model.^4,5  Additionally, all individuals with Paris-Trousseau thrombocytopenia have deletions that are centromeric to FLI1. Interestingly, it has been proposed that transient monoallelic expression of FLI1 is critical for megakaryocyte development. Therefore, when the nonaffected allele is expressed, normal megakaryocyte development occurs; but when the deleted allele is (the one expected to be) expressed, megakaryocyte development is restricted, giving rise to a subpopulation of small megakaryocytes.⁶  Recently, the role of FLI1 and other ETS transcription factors in megakaryopoiesis and platelet function have been underscored by reports of enrichment of FLI1 mutations in individuals with functional platelet defects as well as the recent discovery that mutations in the gene ETV6 also cause thrombocytopenia.^7-9 

In their Brief Report, Stevenson et al describe a family with 2 siblings, affected by a lifelong history of moderate thrombocytopenia and excessive bleeding with seemingly unaffected parents. The patients’ platelets exhibit abnormal response to traditional agonists such as collagen and adenosine diphosphate, and platelet electron micrographs show large, fused electron-dense α-granules characteristic of Paris-Trousseau thrombocytopenia (see figure). Sequencing of FLI1 revealed a homozygous missense mutation at position 970 (c.970C>T) that predicts an arginine to tryptophan substitution in the conserved DNA-binding domain of FLI1.¹ 

Functional analysis of the c.970C>T mutation by a luciferase reporter assay demonstrated decreased transcriptional activity of known gene targets of FLI1, including GP6, GP9, and ITGA2B, with a concomitant reduction of the respective protein expression in the cell lines as well as in platelets of affected individuals, strongly indicating a role of the FLI1 mutation in the platelet phenotype. As the parents do not show a platelet defect despite being heterozygotes for the c.970C>T mutation, the mechanisms that govern the autosomal dominant thrombocytopenia associated with FLI1 hemizygous deletions are still unclear.

Overall, despite robust cumulative genetic and biological evidence pointing to the role of FLI1 in Paris-Trousseau thrombocytopenia, the involvement of other genes in the 11q deletion syndrome could not be ruled out. The report by Stevenson et al, in which a point mutation in FLI1 is associated with the same phenotype, adds strong evidence to the case for FLI1 as the main driver of the Paris-Trousseau thrombocytopenia.