A patient with a typical form of chronic myeloid leukemia was found to carry a large deletion on the derivative chromosome 9q+ and an unusual BCR-ABL transcript characterized by the insertion, ...between BCR exon 14 and ABL exon 2, of 126 bp derived from a region located on chromosome 9, 1.4 Mb 5′ to ABL. This sequence was contained in the bacterial artificial chromosome RP11-65J3, which in fluorescence in situ hybridization experiments on normal metaphases was found to detect, in addition to the predicted clear signal at 9q34, a faint but distinct signal at 22q11.2, where the BCR gene is located, suggesting the presence of a large region of homology between the two chromosomal regions. Indeed, Blast analysis of the RP11-65J3 sequence against the entire human genome revealed the presence of a stretch of homology, about 76 kb long, located approximately 150 kb 3′ to the BCR gene, and containing the 126-bp insertion sequence. Evolutionary studies using fluorescence in situ hybridization identified the region as a duplicon, which transposed from the region orthologous to human 9q34 to chromosome 22 after the divergence of orangutan from the human-chimpanzee-gorilla common ancestor about 14 million years ago. Recent sequence analyses have disclosed an unpredicted extensive segmental duplication of our genome, and the impact of duplicons in triggering genomic disorders is becoming more and more apparent. The discovery of a large duplicon relatively close to the ABL and BCR genes and the finding that the 126-bp insertion is very close to the duplicon at 9q34 open the question of the possible involvement of the duplicon in the formation of the Philadelphia chromosome translocation.
Background:
The aetiology of erythrocytosis is complex; it can be classified as primary or secondary and acquired or congenital. Primary erythrocytosis is a bone marrow disorder caused by an ...intrinsic genetic defect in the erythroid progenitor cell. Secondary erythrocytosis is caused by factors independent of the erythroid compartment, usually causing an increased erythropoietin production. To date, several studies have been performed on large patient cohorts to identify any clinical or laboratory feature helping to distinguish familial and congenital erythrocytosis or primary acquired forms such as polycythemia vera. However, the differential diagnosis of erythrocytosis patients remains complex.
Aims:
The aim of this study was to analyze a group of 15 patients with erythrocytosis by a targeted next generation sequencing (NGS) approach with a customized panel of 26 myeloid genes. All cases were negative for the classic JAK2 V617F mutation, but were characterized by the JAK2 GGCC_46/1 haplotype, a germline combination of polymorphisms known to be associated with the onset of myeloproliferative neoplasms.
Methods:
A targeted NGS approach by Ion Torrent sequencing was employed using a customized panel including 26 genes involved in myeloid malignancies. This gene panel was created using the Ion AmpliSeq Designer (Thermo Fisher). Selected variants were investigated for a potential pathogenetic role using the SIFT and Polyphen scores and the Catalogue of Somatic Mutations in Cancer database.
Results:
Overall, 25 genetic variants in 13 myeloid genes were identified in all 15 patients within the examined cohort. According to their frequency in the healthy population and to a germline or somatic nature in our patient series, these variants were divided into three different groups: polymorphisms, rare germline variants, and rare somatic variants. Overall, seven polymorphisms attributed a benign clinical significance, and having a frequency of 10–40% in healthy individuals, were detected at higher frequency in our patient cohort in the following genes: JAK2 (rs2230724, rs2274649, rs2230722) ANKRD26 (rs7897309), GATA2 (rs2335052), TET2 (rs34402524), and CALR (rs1049481). In addition to polymorphisms, our analysis revealed rare germline and somatic variants in the TET2, KIT, MPL, DNMT3A, FLT3, EZH2, JAK2, ASXL1, ANKRD26, ZRSR2, and RUNX1 genes. At least one rare germline or somatic variant was detected in 13 of the 15 cases (87%), the most frequently mutated genes being TET2 (7/15, 47%), KIT (4/15, 27%), MPL and DNMT3A (3/15, 20%). Non canonical JAK2 K1055R and MPL V114 M variants, mapping in JAK2 exon 23 and MPL exon3, respectively, were identified in 3 patients, one patient showing both.
Summary/Conclusion:
In this NGS study, patients with erythrocytosis lacking known pathogenic driver mutations were almost all (87%) found to be positive for rare variants in myeloid genes. The large number of rare germline variants together with polymorphisms in the JAK2, ANKRD26, GATA2, TET2, and CALR genes is in accordance with the co‐occurrence of the JAK2 GGCC germline haplotype, that seems to predispose to an increased risk of developing erythrocytosis. However, the pathogenic contribution of each identified new gene variant warrants further investigations.
Italie année zéro Avoledo, Tullio; Baghetti, Carlo; Bajani, Andrea ...
2018
Book
Odprti dostop
Écrits entre 2005 et 2015, en prise avec une réalité qui dépasse les frontières de l’Italie, les textes réunis ici mettent en histoire les vies de femmes et d’hommes qui incarnent la flexibilité, le ...chômage, la précarité et donnent un visage à la crise. Gramsci les nommait les « subalternes », le néoréalisme les « anonymes », Pasolini les « sous-prolétaires » ; ils ont été les « vaincus », les « humbles », les « déshérités », ils sont aujourd’hui les « équilibristes », les « derniers », les « précaires », personnages socialement invisibles, mais au premier plan de la littérature, du théâtre et du cinéma de l’Italie d’aujourd’hui. Ils sont peintres, maçons, élagueurs ou danseurs, stagiaires, étudiants ou migrants, aux prises avec l’injustice, avec la difficulté de vivre, de travailler, d’espérer et d’aimer. Italie année zéro. Chroniques de la crise démontre en douze récits comment la littérature italienne contemporaine prend en charge les questions liées à la crise économique et à l’évolution du monde du travail : une écriture qui sait mêler avec brio récit et document, intime et collectif, littérature du réel et histoire immédiate.
Combinaisons de papier Zagaria, Cristina
Presses universitaires de Paris Nanterre eBooks,
2018
Book Chapter
Odprti dostop
Soit nous nous relevons en tant quʼéquipe, soit nous nous écroulons, centimètre après centimètre, jeu après jeu, jusquʼà la fin… Nous sommes en enfer, Messieurs. Croyez-moi. Nous pouvons y rester, ...nous prendre des baffes… Ou bien nous pouvons nous battre et revenir dans la lumière. Nous pouvons escalader les murs de lʼenfer centimètre par centimètre. Al Pacino, LʼEnfer du dimanche 6 heures « Salut Bruno ! – Salut Ale ! – Salut Ciccio ! » Salut. Trois cents saluts. Un à la fois. Pour nous ente...
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