Contributions
Abstract: O11
Type: Oral presentation
Session Topic: Inherited and acquired disorders of platelets
Presentation during EHA Scientific Conference on Bleeding Disorders:
On Thursday, September 15, 2016 from 09:00 - 10:30
Location: Rossini 1
Background
In 2015, different studies disclosed that mutations in the gene ETV6 are responsible for a new form of IT and suggested that ETV6-RT predisposes to hematological malignancies1-2.
Aims
To gain further information on this new IT, in particular on the predisposition to hematological malignancies, in order to reach a clinical and pathogenetic characterization.
Methods
We enrolled 130 unrelated patients with ITs investigated at the IRCCS Policlinico San Matteo Foundation of Pavia, Italy. All of them had no definite diagnosis because they did not fit the criteria for any known IT3. They were part of our series of 274 consecutive propositi analyzed in our institution from 2003 to 2014. Whenever ETV6 mutations were identified, the available relatives of probands were studied. ETV6 mutations were investigated by WES or Sanger sequencing. Each patient underwent phenotypic characterization (blood cell counts and platelet size; platelet flow cytometry; platelet aggregation; platelet activation; platelet adhesion and spreading; differentiation of human megakaryocytes and morphological analysis; megakaryocyte flow cytometry; evaluation of proplatelet formation by in vitro differentiated megakaryocytes).
Results
We identified 20 subjects from 7 families bearing 5 different ETV6 mutations. The bleeding tendency and the degree of thrombocytopenia were mild, but we found that 4 of 20 patients (20%) had ALL, thus confirming that early leukemic transformation is a major risk of this IT. Moreover, we found that one patient developed JAK2 positive polycythemia vera at age 37, suggesting that this disease should be added to the list of malignancies to which the ETV6-RT predisposes. Our study did not identify any peculiar feature that can be used to raise the suspicion of ETV6-RT and the diagnosis is therefore difficult. Moreover, we did not identify any distinguishing defect of major platelet GPs or in vitro platelet aggregation. Also evaluation of peripheral blood films did not found any morphological abnormality, apart from platelet anisocytosis and an increased percentage of large platelets, which are common to the majority of ITs. However, at variance with most ITs, MPD and MPV were consistently normal in ETV6-RT, and it is just the normal size of platelets that should rise suspicion of this condition in subjects with an autosomal dominant thrombocytopenia. This finding is shared with ITs due to monoallelic mutations in RUNX1 and ANKRD26, which also have normal platelet size and predispose to leukemia. In vitro studies revealed that patient megakaryocytes have defective maturation and proplatelet formation, while platelets have reduced ability to spread on fibrinogen, thus suggesting some functional platelets defect. We found also that ETV6-RT is relatively frequent: in fact, in our series, ETV6-RT had a relative prevalence of 2.9% in the whole case series, and of 4.6% in the series of patients with known ITs. Its frequency was lower only to that of monoallelic BSS, MYH9-RT, ANKRD26-RT and biallelic BSS.
Conclusions
Monoallelic ETV6 mutations cause one of the most frequent forms of ITs, without large platelets, and confirmed that affected subjects have high propensity to hematological malignancies, in particular childhood ALL. Since the only dominant ITs without platelet macrocytosis are ETV6-RT, FDP/AML, and ANKRD26-RT, we suggest that all subjects with a dominant IT and normal platelet size should be tested for mutation in these genes.
References
1. Noetzli L et al. Nat Genet. 2015;47(5):535-538.
2. Zhang MY et al. Nat Genet. 2015;47(2):180-185.
3. Pecci A. Clin Genet. 2016;89(2):141-153
Abstract: O11
Type: Oral presentation
Session Topic: Inherited and acquired disorders of platelets
Presentation during EHA Scientific Conference on Bleeding Disorders:
On Thursday, September 15, 2016 from 09:00 - 10:30
Location: Rossini 1
Background
In 2015, different studies disclosed that mutations in the gene ETV6 are responsible for a new form of IT and suggested that ETV6-RT predisposes to hematological malignancies1-2.
Aims
To gain further information on this new IT, in particular on the predisposition to hematological malignancies, in order to reach a clinical and pathogenetic characterization.
Methods
We enrolled 130 unrelated patients with ITs investigated at the IRCCS Policlinico San Matteo Foundation of Pavia, Italy. All of them had no definite diagnosis because they did not fit the criteria for any known IT3. They were part of our series of 274 consecutive propositi analyzed in our institution from 2003 to 2014. Whenever ETV6 mutations were identified, the available relatives of probands were studied. ETV6 mutations were investigated by WES or Sanger sequencing. Each patient underwent phenotypic characterization (blood cell counts and platelet size; platelet flow cytometry; platelet aggregation; platelet activation; platelet adhesion and spreading; differentiation of human megakaryocytes and morphological analysis; megakaryocyte flow cytometry; evaluation of proplatelet formation by in vitro differentiated megakaryocytes).
Results
We identified 20 subjects from 7 families bearing 5 different ETV6 mutations. The bleeding tendency and the degree of thrombocytopenia were mild, but we found that 4 of 20 patients (20%) had ALL, thus confirming that early leukemic transformation is a major risk of this IT. Moreover, we found that one patient developed JAK2 positive polycythemia vera at age 37, suggesting that this disease should be added to the list of malignancies to which the ETV6-RT predisposes. Our study did not identify any peculiar feature that can be used to raise the suspicion of ETV6-RT and the diagnosis is therefore difficult. Moreover, we did not identify any distinguishing defect of major platelet GPs or in vitro platelet aggregation. Also evaluation of peripheral blood films did not found any morphological abnormality, apart from platelet anisocytosis and an increased percentage of large platelets, which are common to the majority of ITs. However, at variance with most ITs, MPD and MPV were consistently normal in ETV6-RT, and it is just the normal size of platelets that should rise suspicion of this condition in subjects with an autosomal dominant thrombocytopenia. This finding is shared with ITs due to monoallelic mutations in RUNX1 and ANKRD26, which also have normal platelet size and predispose to leukemia. In vitro studies revealed that patient megakaryocytes have defective maturation and proplatelet formation, while platelets have reduced ability to spread on fibrinogen, thus suggesting some functional platelets defect. We found also that ETV6-RT is relatively frequent: in fact, in our series, ETV6-RT had a relative prevalence of 2.9% in the whole case series, and of 4.6% in the series of patients with known ITs. Its frequency was lower only to that of monoallelic BSS, MYH9-RT, ANKRD26-RT and biallelic BSS.
Conclusions
Monoallelic ETV6 mutations cause one of the most frequent forms of ITs, without large platelets, and confirmed that affected subjects have high propensity to hematological malignancies, in particular childhood ALL. Since the only dominant ITs without platelet macrocytosis are ETV6-RT, FDP/AML, and ANKRD26-RT, we suggest that all subjects with a dominant IT and normal platelet size should be tested for mutation in these genes.
References
1. Noetzli L et al. Nat Genet. 2015;47(5):535-538.
2. Zhang MY et al. Nat Genet. 2015;47(2):180-185.
3. Pecci A. Clin Genet. 2016;89(2):141-153