Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia

@article{Noetzli2015GermlineMI,
  title={Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia},
  author={Leila J. Noetzli and Richard W. Lo and Alisa B. Lee-Sherick and Michael U Callaghan and Patrizia Noris and Anna Savoia and Madhvi Rajpurkar and Kenneth L Jones and Katherine Gowan and Carlo L. Balduini and Alessandro Pecci and Chiara Gnan and Daniela De Rocco and Michael Doubek and Ling Li and Lily Y. Lu and Richard S. Leung and Carolina Landolt-Marticorena and Stephen P. Hunger and Paula G. Heller and Arthur Gutierrez-Hartmann and Liang Xiayuan and Fred G Pluthero and Jesse W. Rowley and Andrew S. Weyrich and Walter H A Kahr and Christopher C Porter and Jorge Di Paola},
  journal={Nature genetics},
  year={2015},
  volume={47},
  pages={535 - 538}
}
Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell–precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain… Expand
Germline ETV6 mutations and predisposition to hematological malignancies
TLDR
The role of ETV6 in hematopoiesis, especially in myeloid differentiation and maturation, is focused upon, and the functional effects of mutant ETV 6 are described. Expand
Functional analysis of germline ETV6 W380R mutation causing inherited thrombocytopenia and secondary acute lymphoblastic leukemia or essential thrombocythemia
TLDR
Functional validation of ETV6 W380R mutation segregating with thrombocytopenia in a family where two family members also suffered from acute lymphoblastic leukemia (ALL) or essential thromBocythemia (ET) predicted impaired DNA binding due to W 380R mutation. Expand
ETV6-related thrombocytopenia and platelet dysfunction
TLDR
ETV6 germline mutations represent a new cancer predisposition thrombocytopenia with platelet dysfunction with preliminary data suggest that decreased ETV6 function leads to MK maturation arrest, impaired platelet production and differentially expressed platelet transcripts among individuals affected with ETV 6 mutations when compared to control relatives. Expand
Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia
Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here weExpand
Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia
TLDR
The clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6 are described. Expand
Functional characterization of a germline ETV6 variant associated with inherited thrombocytopenia, acute lymphoblastic leukemia, and salivary gland carcinoma in childhood
TLDR
The findings suggest that the ETV6 gene should be sequenced in patients with inherited thrombocytopenia and malignancy, and emphasize the importance of careful follow-up to identify secondary cancer in Patients with pathogenic ETV 6 variants. Expand
Novel phenotypes observed in patients with ETV6-linked leukaemia/familial thrombocytopenia syndrome and a biallelic ARID5B risk allele as leukaemogenic cofactor
TLDR
A novel clinical and laboratory phenotypes of seven individuals from three families with ETV6 germline mutations and a refined genetic analysis of one child with additional high-hyperdiploid acute lymphoblastic leukaemia (HD-ALL), aiming to elucidate second oncogenic hits are presented, propose ARID5B as potential leukaemogenic cofactor in patients with E TV6-linked leukaemic predisposition and familial thrombocytopenia syndrome. Expand
Inherited Thrombocytopenias with Predisposition the Hematological Malignancies
Inherited thrombocytopenias (IT) are rare, clinically and genetically heterogeneous diseases caused by mutations in more than 30 genes. Mutations of three of these genes, RUNX1, ANKRD26, and ETV6,Expand
Predisposition to childhood acute lymphoblastic leukemia caused by a constitutional translocation disrupting ETV6.
TLDR
It is suggested that germline aberrations resulting in monoallelic expression of ETV6 contribute to leukemia susceptibility, whereas more severe functional deficiency of E TV6 is required for developing THC5. Expand
Detection of a new heterozygous germline ETV6 mutation in a case with hyperdiploid acute lymphoblastic leukemia
TLDR
A new pedigree with a germline ETV6 mutation is reported in which the index patient and his father developed high hyperdiploid (HeH) ALL and polycythemia vera at age 13 and 51, respectively. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 41 REFERENCES
Clinical effect of point mutations in myelodysplastic syndromes.
TLDR
Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with myelodysplastic syndromes, independently of established risk factors. Expand
Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia
TLDR
The findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia. Expand
Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy
TLDR
Functional studies show that a central role for ETV6 in hematopoiesis and malignant transformation is identified, and the identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals. Expand
Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia
TLDR
ETV6 abnormalities are not restricted to translocations and occur more frequently in AML than previously thought, and one-third of AML patients have deficient ETV6 protein expression, which is not related to ETV 6 mRNA expression levels. Expand
Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia
TLDR
It is suggested that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis and the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer. Expand
Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1
TLDR
A family with X-linked dyserythropoietic anaemia and thrombocytopenia due to a substitution of methionine for valine at amino acid 205 of GATA-1 is described and the importance of FOG-1, Gata-1 associations in both megakaryocyte and erythroid development, is underscored. Expand
PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13)
TLDR
There is strong evidence that the PAX5/ETV6 fusion transcript defines the clinical and biological entity that is associated with the presence of a dic(9;12) chromosome. Expand
FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia.
TLDR
The role of transient monoallelic expression of a gene essential for differentiation in the genesis of human haploinsufficiency-associated disease is pointed to and such a mechanism may be involved in the pathogenesis of other congenital or acquired genetic diseases. Expand
Abnormal RNA processing due to the exon mutation of βE-globin gene
TLDR
It is reported here that the complete nucleotide sequence of a βE-gene revealed the expected GAG → AAG change in codon 26 but no other mutations, demonstrating a disturbance in the expression of the βE -gene attributable solely to the exon mutation—a novel mechanism for gene dysfunction. Expand
Abnormal RNA processing due to the exon mutation of beta E-globin gene.
TLDR
It is reported here that the complete nucleotide sequence of a beta E-gene revealed the expected GAG leads to AAG change in codon 26 but no other mutations, demonstrating a disturbance in the expression of the beta E -gene attributable solely to the exon mutation-a novel mechanism for gene dysfunction. Expand
...
1
2
3
4
5
...