5′UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia

Thrombocytopenia 2 (THC2) is an inherited disorder caused by monoallelic single nucleotide substitutions in the 5'UTR of the ANKRD26 gene. Patients have thrombocytopenia and increased risk of myeloid malignancies, in particular, acute myeloid leukemia (AML). Given the association of variants in the ANKRD26 5'UTR with myeloid neoplasms, we investigated whether, and to what extent, mutations in this region contribute to apparently sporadic AML. To this end, we studied 250 consecutive, non-familial, adult AML patients and screened the first exon of ANKRD26 including the 5'UTR. We found variants in four patients. One patient had the c.-125T>G substitution in the 5'UTR, while three patients carried two different variants in the 5' end of the ANKRD26 coding region (c.3G>A or c.105C>G). Review of medical history showed that the patient carrying the c.-125T>G was actually affected by typical but unrecognized THC2, highlighting that some apparently sporadic AML cases represent the evolution of a well-characterized familial predisposition disorder. As regards the c.3G>A and the c.105C>G, we found that both variants result in the synthesis of N-terminal truncated ANKRD26 isoforms, which are stable and functional in cells, in particular, have a strong ability to activate the MAPK/ERK signaling pathway. Moreover, investigation of one patient with the c.3G>A showed that mutation was associated with strong ANKRD26 overexpression in vivo, which is the proposed mechanism for predisposition to AML in THC2 patients. These data provide evidence that N-terminal ANKRD26 truncating mutations play a potential pathogenetic role in AML. Recognition of AML patients with germline ANKRD26 pathogenetic variants is mandatory for selection of donors for bone marrow transplantation

Dysregulation of oncogenic factors by GFI1B p32: investigation of a novel GFI1B germline mutation

GFI1B is a transcription factor essential for the regulation of erythropoiesis and megakaryopoiesis, and pathogenic variants have been associated with thrombocytopenia and bleeding. Analysing thrombocytopenic families by whole exome sequencing, we identified a novel GFI1B variant (c.648+5G>A), which causes exon 9 skipping and overexpression of a shorter p32 isoform. We report the clinical data of our patients and critically review the phenotype observed in individuals with different GFI1B variants leading to the same effect on the p32 expression. Since p32 is increased in acute and chronic leukemia cells, we tested the expression level of genes playing a role in various type of cancers, including hematological tumors and found that they are significantly dysregulated, suggesting a potential role for GFI1B in carcinogenesis regulation. Increasing the number of individuals with GFI1B variants will allow us to better characterize this rare disease and determine whether it is associated with an increased risk of developing malignancies

Research at the heart of hematology: Thrombocytopenias and platelet function disorders

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Platelets in Thrombotic and Non-Thrombotic Disorders Pathophysiology, Pharmacology and Therapeutics: an Update

Inherited thrombocytopenias are a heterogeneous group of disorders with different degrees of severity and complexity deriving from mutations in at least 25 genes. Only a few inherited thrombocytopenias are characterized by recurrent spontaneous hemorrhages due to a very low platelet count and/or associated platelet dysfunction, while the other forms expose patients to the risk of bleeding in connection with hemostatic challenges. Some of the genetic abnormalities resulting in thrombocytopenia also cause additional congenital defects. Moreover, some common forms of inherited thrombocytopenia predispose to acquire in childhood or adult life additional serious diseases, as bone marrow aplasia, hematological malignancies, or kidney failure. Making a definite diagnosis is difficult and requires a close collaboration of clinicians, lab technicians, and geneticists. Many therapeutic measures are available both for preventing and stopping bleeding. Different treatments are available also for many congenital or acquired defects that may associate with thrombocytopenia

Inherited thrombocytopenias—recent advances in clinical and molecular aspects

Since the beginning of the century, our knowledge of inherited thrombocytopenias greatly advanced, and we presently know 30 forms with well-defined genetic defects. This great advancement changed our view of these disorders, as we realized that most patients have only mild thrombocytopenia with inconspicuous bleeding or no bleeding tendency at all. However, better knowledge of inherited thrombocytopenias also revealed that some of the most prevalent forms expose to the risk of acquiring during infancy or adulthood additional disorders that endanger the life of patients much more than hemorrhages. Thus, inherited thrombocytopenias are complex disorders with quite different clinical features and prognosis. Identification of novel genes whose mutations result in low platelet count greatly advanced also our knowledge of the megakaryocyte biology and proved beyond any doubt that the defective proteins play an essential role in platelet biogenesis or survival in humans. Based on the study of inherited thrombocytopenias, we better understood the sequence of molecular events regulating megakaryocyte differentiation, maturation, and platelet release. Since nearly 50% of patients have as yet unidentified genetic or molecular mechanisms underlying their inherited thrombocytopenia, further studies are expected to reveal new clinical entities and new molecular mechanisms of platelet production

New roles for mean platelet volume measurement in the clinical practice?

Several hundreds of studies recently investigated mean platelet volume (MPV) as measured by electronic cell counters in a wide variety of acquired diseases, and most of them found that platelet size was significantly increased with respect to healthy subjects. On this basis, it has been suggested that MPV can be used for diagnostic purposes. Moreover, investigation of subjects with arterial thrombosis not only revealed that their platelets were larger than those of controls, but also found that a high MPV predicted poor prognosis. Despite the large amount of available data, the pathogenesis of increased platelet size in these conditions is unclear. In particular, we do not know whether the increased platelet size is the cause or the consequence of thrombosis. Differences in MPV between patients and controls are usually very small and they reach the statistical significance because of the large number of investigated patients and the standardized methodology for MPV measurement. In real life, the wide variability of MPV possibly due to platelet count, sex, age, and ethnicity, as well as the very poor standardization of the methodologies used for MPV measurement, makes it impossible to decide whether an individual patient has normal or instead slightly increased MPV. So, MPV has presently no role in making diagnosis and defining prognosis in any acquired illness

Venous thromboembolism in chronic gastrointestinal disorders

Chronic gastrointestinal disorders (including autoimmune gastritis, celiac disease, inflammatory bowel disease, and diverticular disease) are highly prevalent disorders, that may be associated with unpredictable, life-threatening complications, such as thromboembolic events. Venous thromboembolism (VTE) is one of the major causes of morbidity and mortality worldwide. Several conditions, including cancer, major trauma, surgery, prolonged immobilization, are well-established risk factors for VTE. Over the past decade, chronic inflammation has also been identified as an independent risk factor for VTE due to the prothrombotic effects of inflammatory cytokines and oxidative stress on the coagulation cascade. Other several mechanisms were shown to be associated with a higher incidence of VTE in patients with gastrointestinal disorders

Corrigendum: Diagnostic Delay of Pulmonary Embolism in COVID-19 Patients

: [This corrects the article DOI: 10.3389/fmed.2021.637375.]