ETV6-RELATED THROMBOCYTOPENIA (ETV6-RT): CLINICAL AND PATHOGENETIC CHARACTERIZATION OF AN INHERITED THROMBOCYTOPENIA (IT) PREDISPOSING TO CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)
Author(s): ,
Federica Melazzini
Affiliations:
Internal Medicine,IRCCS Policlinico San Matteo Foundation, University of Pavia,Pavia,Italy
,
Daniela De Rocco
Affiliations:
Medical Sciences,University of Trieste,Trieste,Italy;Institute for Maternal and Child Health- IRCCS Burlo Garofolo,Trieste,Italy
,
Caterina Marconi
Affiliations:
Medical and Surgical Science,Policlinico Sant’Orsola Malpighi and University of Bologna,Bologna,Italy
,
Christian Di Buduo
Affiliations:
Molecular Medicine,University of Pavia,Pavia,Italy
,
Patrizia Noris
Affiliations:
Internal Medicine,IRCCS Policlinico San Matteo Foundation, University of Pavia,Pavia,Italy
,
Michela Falaschini
Affiliations:
Medical Sciences,University of Trieste,Trieste,Italy;Institute for Maternal and Child Health- IRCCS Burlo Garofolo,Trieste,Italy
,
Tommaso Pippucci
Affiliations:
Medical and Surgical Science,Policlinico Sant’Orsola Malpighi and University of Bologna,Bologna,Italy
,
Alessandra Balduini
Affiliations:
Molecular Medicine,University of Pavia,Pavia,Italy
,
Alessandro Pecci
Affiliations:
Internal Medicine,IRCCS Policlinico San Matteo Foundation, University of Pavia,Pavia,Italy
,
Chiara Gnan
Affiliations:
Medical Sciences,University of Trieste,Trieste,Italy;Institute for Maternal and Child Health- IRCCS Burlo Garofolo,Trieste,Italy
,
Flavia Palombo
Affiliations:
Medical and Surgical Science,Policlinico Sant’Orsola Malpighi and University of Bologna,Bologna,Italy
,
Serena Barozzi
Affiliations:
Internal Medicine,IRCCS Policlinico San Matteo Foundation, University of Pavia,Pavia,Italy
,
Caterina Alfano
Affiliations:
Medical Sciences,University of Trieste,Trieste,Italy;Institute for Maternal and Child Health- IRCCS Burlo Garofolo,Trieste,Italy
,
Valeria Bozzi
Affiliations:
Internal Medicine,IRCCS Policlinico San Matteo Foundation, University of Pavia,Pavia,Italy
,
Elisa Civaschi
Affiliations:
Internal Medicine,IRCCS Policlinico San Matteo Foundation, University of Pavia,Pavia,Italy
,
Elena Cigalini
Affiliations:
Internal Medicine,IRCCS Policlinico San Matteo Foundation, University of Pavia,Pavia,Italy
,
Anna Savoia
Affiliations:
Medical Sciences,University of Trieste,Trieste,Italy;Institute for Maternal and Child Health- IRCCS Burlo Garofolo,Trieste,Italy
,
Marco Seri
Affiliations:
Medical and Surgical Science,Policlinico Sant’Orsola Malpighi and University of Bologna,Bologna,Italy
,
Michel Doubek
Affiliations:
Internal Medicine, Haematology/Oncology,University Hospital Brno,Brno,Czech Republic
,
Giuseppe Loffredo
Affiliations:
Oncology,Azienda Santobono Pausilipon, Pausilipon Hospital, Naples,Naples,Italy
Carlo Luigi Balduini
Affiliations:
Internal Medicine,IRCCS Policlinico San Matteo Foundation, University of Pavia,Pavia,Italy
(Abstract release date: 05/19/16) EHA Library. Melazzini F. 06/10/16; 135181; S148 Disclosure(s): IRCCS Policlinico San Matteo Foundation, University of Pavia
Dr. Federica Melazzini
Dr. Federica Melazzini
Contributions
Abstract
Abstract: S148

Type: Presidential Symposium

Presentation during EHA21: On Friday, June 10, 2016 from 16:22 - 16:35

Location: Hall A1

Background
ETV6-RT is an autosomal dominant IT recently identified in a few families and suspected to predispose to hematological malignancies.

Aims
To gain information on the clinical and laboratory picture of this new IT, in particular on predisposition to hematological malignancies.

Methods
130 unrelated and consecutive patients with ITs were enrolled to the study: all of them had no definite diagnosis because they did not fit the criteria for any known IT. ETV6 mutations were investigated by whole exome sequencing (84 probands) or Sanger sequencing (46 probands): whenever ETV6 mutations were identified, all available relatives of probands were also investigated. 5 patients from 2 known ETV6-RT families already partially described (Noetzli L et al, Nat Genet 2015, 47:535) were also included. Each patient underwent to phenotypic characterization through the following investigations: complete blood count and platelet sizing, flow cytometry of platelet membrane glycoproteins, “in vitro” platelet aggregation, platelet activation, platelet adhesion and spreading, differentiation of human megakaryocytes (Mks) and morphological analysis, Mk flow cytometry, evaluation of proplatelet formation by in vitro differentiated Mks.

Results
Overall, 20 subjects from 7 families bearing 5 different ETV6 mutations were identified. The bleeding tendency and the degree of thrombocytopenia were mild, but we found that 4 of 20 patients (20%) had childhood ALL, thus confirming that early leukemic transformation is a major risk of this IT. Moreover, one patient developed JAK2 polycythemia vera at age 37, suggesting that this disease should be added to the list of malignancies to which the ETV6-RT predisposes. Clinical and laboratory findings (platelet aggregation, surface glycoproteins, activation and adhesion) did not identify any peculiar defect that can be used to suspect this disorder. In vitro studies revealed that patient Mks have defective maturation and proplatelet formation, while platelets have reduced ability to spread on fibrinogen. At variance with most ITs, platelet size was not enlarged: this finding is shared with ITs due to monoallelic mutations in RUNX1 and ANKRD26, which also have normal platelet size and predispose to leukemia (the familial platelet disorder with predisposition to acute myeloid leukemia, and the ANKRD26-RT, respectively). Considering the possibility that patients with ITs have ETV6-RT is important both for the risk to develop hematological malignancies, and because this disorder is relatively frequent: in our series of 274 consecutive propositi, ETV6-RT was identified in 8 families and had, therefore, a relative prevalence of 2.9% in the whole case series, and of 6.1% in the series of patients with known ITs. In our experience, the frequency of ETV6-RT was lower only to that of monoallelic Bernard-Soulier syndrome (BSS, 12.2% in the whole series), MYH9-related disease (11.4%), ANKRD26-RT (9.4%), and biallelic BSS (5.7%).

Conclusion
Our study showed that monoallelic ETV6 mutations cause one of the most frequent forms of ITs and confirmed that affected subjects have little bleeding tendency but high propensity to hematological malignancies, in particular childhood ALL. Since ETV6-RT is one of the few autosomal dominant forms of IT without platelet macrocytosis, the screening for ETV6 mutations is recommended in all patients with these characteristics, along with the screening for  RUNX1 and ANKRD26  mutations.

Session topic: Presidential Symposium

Keyword(s): ALL, Genetic, Platelet, Thrombocytopenia
Abstract: S148

Type: Presidential Symposium

Presentation during EHA21: On Friday, June 10, 2016 from 16:22 - 16:35

Location: Hall A1

Background
ETV6-RT is an autosomal dominant IT recently identified in a few families and suspected to predispose to hematological malignancies.

Aims
To gain information on the clinical and laboratory picture of this new IT, in particular on predisposition to hematological malignancies.

Methods
130 unrelated and consecutive patients with ITs were enrolled to the study: all of them had no definite diagnosis because they did not fit the criteria for any known IT. ETV6 mutations were investigated by whole exome sequencing (84 probands) or Sanger sequencing (46 probands): whenever ETV6 mutations were identified, all available relatives of probands were also investigated. 5 patients from 2 known ETV6-RT families already partially described (Noetzli L et al, Nat Genet 2015, 47:535) were also included. Each patient underwent to phenotypic characterization through the following investigations: complete blood count and platelet sizing, flow cytometry of platelet membrane glycoproteins, “in vitro” platelet aggregation, platelet activation, platelet adhesion and spreading, differentiation of human megakaryocytes (Mks) and morphological analysis, Mk flow cytometry, evaluation of proplatelet formation by in vitro differentiated Mks.

Results
Overall, 20 subjects from 7 families bearing 5 different ETV6 mutations were identified. The bleeding tendency and the degree of thrombocytopenia were mild, but we found that 4 of 20 patients (20%) had childhood ALL, thus confirming that early leukemic transformation is a major risk of this IT. Moreover, one patient developed JAK2 polycythemia vera at age 37, suggesting that this disease should be added to the list of malignancies to which the ETV6-RT predisposes. Clinical and laboratory findings (platelet aggregation, surface glycoproteins, activation and adhesion) did not identify any peculiar defect that can be used to suspect this disorder. In vitro studies revealed that patient Mks have defective maturation and proplatelet formation, while platelets have reduced ability to spread on fibrinogen. At variance with most ITs, platelet size was not enlarged: this finding is shared with ITs due to monoallelic mutations in RUNX1 and ANKRD26, which also have normal platelet size and predispose to leukemia (the familial platelet disorder with predisposition to acute myeloid leukemia, and the ANKRD26-RT, respectively). Considering the possibility that patients with ITs have ETV6-RT is important both for the risk to develop hematological malignancies, and because this disorder is relatively frequent: in our series of 274 consecutive propositi, ETV6-RT was identified in 8 families and had, therefore, a relative prevalence of 2.9% in the whole case series, and of 6.1% in the series of patients with known ITs. In our experience, the frequency of ETV6-RT was lower only to that of monoallelic Bernard-Soulier syndrome (BSS, 12.2% in the whole series), MYH9-related disease (11.4%), ANKRD26-RT (9.4%), and biallelic BSS (5.7%).

Conclusion
Our study showed that monoallelic ETV6 mutations cause one of the most frequent forms of ITs and confirmed that affected subjects have little bleeding tendency but high propensity to hematological malignancies, in particular childhood ALL. Since ETV6-RT is one of the few autosomal dominant forms of IT without platelet macrocytosis, the screening for ETV6 mutations is recommended in all patients with these characteristics, along with the screening for  RUNX1 and ANKRD26  mutations.

Session topic: Presidential Symposium

Keyword(s): ALL, Genetic, Platelet, Thrombocytopenia

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies