Submitted by admin tede (tede@pucgoias.edu.br) on 2018-06-20T19:01:11Z No. of bitstreams: 1 ANDREYA GONÇALVES COSTA MOTTA.pdf: 1269655 bytes, checksum: d3b8bb83fce2a80358844cba4c05d288 (MD5) / Made available in DSpace on 2018-06-20T19:01:11Z (GMT). No. of bitstreams: 1 ANDREYA GONÇALVES COSTA MOTTA.pdf: 1269655 bytes, checksum: d3b8bb83fce2a80358844cba4c05d288 (MD5) Previous issue date: 2018-03-08 / The understanding of the biological effects radioinducites in the organism can help the cytogenetic dosimetry in monitoring the health of professionals occupationally exposed to radiation, so radiology technicians must pay attention to all necessary and obligatory measures of protection because they are responsible for the procedures that refer to the diagnoses involving exposure to ionizing radiation. The objective of this research was to perform a cytogenetic analysis of 20 professional radiology technicians exposed occupationally to ionizing radiation through the collection of heparinized peripheral blood and culture of T lymphocytes to verify the frequencies of chromosomal aberrations and micronuclei. All subjects had to have more than 3 years of service time, regardless of age, sex, smoking habits or alcohol. The control group had the same age and sex as the exposed group. Micronucleus analysis occurred faster and more accurately than the analysis of chromosomal aberrations, suggesting that it is used as the first choice in radiological screening. Metaphase analysis and the cytokinesis blockade test allowed the quantification of a high frequency of unstable chromosomal aberrations and micronuclei in subjects with a workday from 6 hours to 12 hours daily. The results of the frequency of unstable chromosomal aberrations in the exposed group were 0.031 ± 0.030 and in the control group 0.002 ± 0.004. In the micronuclei frequencies of the exposed group the obtained result was 0.0035 ± 0.003 and in the control group 0,0004 ± 0.001 confirming the methodology of cytogenetic analysis as quality control in the biodosimetric investigation for the identification and prevention of possible genomic damages. Subsequent studies are needed to find out if factors such as smoking and alcoholism can influence changes in the health of these professionals. / A compreensão dos efeitos biológicos radioinduzidos no organismo pode auxiliar a dosimetria citogenética no monitoramento da saúde dos profissionais ocupacionalmente expostos a radiação, assim, os técnicos em radiologia devem se atentar a todas as medidas necessárias e obrigatórias de proteção por serem responsáveis pelos procedimentos que referentes aos diagnósticos clínicos que envolvam a exposição à radiação ionizante. O objetivo desta pesquisa foi realizar análise citogenética de 20 profissionais técnicos em radiologia expostos ocupacionalmente a radiação ionizante, através da coleta de sangue periférico heparinizado e cultura de linfócitos T para verificar as frequências de aberrações cromossômicas e de micronúcleos. Todos os indivíduos tinham que ter mais de 3 anos de tempo de serviço, independente da idade, sexo, hábitos tabagista ou etilista. O grupo controle teve a idade e sexo equiparados com o grupo exposto. A análise de micronúcleos ocorreu de forma mais rápida e precisa do que a análise de aberrações cromossômicas, sugerindo que ela seja utilizada como primeira escolha em triagem radiológica. A análise de metáfases e o teste de bloqueio de citocinese permitiu a quantificação de uma alta frequência de aberrações cromossômicas instáveis e de micronúcleos nos indivíduos com a jornada de trabalho entre 6 horas a 12 horas diárias. Os resultados encontrados da frequência de aberrações cromossômicas instáveis no grupo exposto foi 0,031±0,030 e no grupo controle 0,002±0,004. Nas frequências de micronúcleos do grupo exposto o resultado obtido foi 0,0035±0,003 e no grupo controle 0,0004±0,001 confirmando a metodologia de análise citogenética como controle de qualidade na investigação biodosimétrica para a identificação e prevenção de possíveis danos genômicos. Estudos subsequentes são necessários para averiguar se fatores como o fumo e o etilismo podem influenciar as alterações na saúde destes profissionais.

Genetic changes are hallmarks of cancer development involving the activation and/or inactivation of oncogenes and tumour suppressor genes, respectively. In non-melanoma skin cancer (NMSC) development, the initiation of genetic mutations results from exposure to solar ultraviolet radiation. Non-melanoma skin cancers are comprised of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Several related cutaneous lesions also exist, of which solar keratoses (SK) are widely accepted as a precursor dysplasia to SCC development. The study of recurrent genetic changes present within NMSC and SK should help reveal causative mutations in skin cancer development. Such analysis could also elucidate links in the genetic similarity of these dysplasia. The rapid screening of numerical changes in DNA sequence copy number throughout the entire genome has been made possible by the advent of comparative genomic hybridisation (CGH). This technique enables the identification of net gains and loss of genetic material within a tumour DNA sample. Chromosomal regions of recurrent gain or loss identify loci containing putative oncogenes and tumour suppressor genes, respectively with potential roles in NMSC tumourigenesis. Used in conjunction with tissue microdissection and universal degenerate PCR techniques this can enable the elucidation of aberrations in small histologically distinct regions of tumour. Such a technique can utilize archival material such as paraffin embedded tissue, which is the major source of neoplastic material available for cancer research. This study used the CGH technique to investigate aberrations in BCC, SCC and SK samples. The screening of copy number abnormalities (CNAs) in BCC revealed that although these tumours were close to diploid and generally genetically stable, they did contain several recurrent aberrations. The loss of genetic material at 9q was identified in a third of BCC tumours studied. This is characteristic of inactivation of the PTCH tumour suppressor gene, a known attribute in some sporadic BCC development. Validation of this loss was performed via loss of heterozygosity, demonstrating good concordance with the CGH data. In addition the over-representation of the 6p chromosome arm was revealed in 47% of biopsies. This novel CNA is also commonly observed in other cutaneous neoplasias, including Merkel cell carcinoma and malignant melanoma. This suggests a possible common mechanism in development and or promotion in these cutaneous dysplasias, the mechanisms of which have yet to be clearly defined. In contrast to BCC, numerical genetic aberrations in SCC and SK were much more frequent. Several regions of recurrent gain were commonly shared between both dysplasias including gain of 3q, 4p, 5p, 8q, 9q, 14q, 17p, 17q and 20q. Common chromosomal regions of loss included 3p, 8p, 9p, 11p, 13q and 17p. In addition loss of chromosome 18 was significantly observed in SCC in comparison to SK, a possible defining event in SK progression to SCC. The identification of shared genetic aberrations suggests a clonal and genetic relationship between the two lesions. This information further supports the notion for re-classification of SK to an SCC in situ or superficial SCC. Finally, the CNAs detected have been similarly observed in other squamous cell-derived tumours, for example cervical and head and neck SCC. This provides further evidence to common mechanisms involved in the initiation, development and progression of SCC neoplasia. This study has identified a number of recurrent chromosomal regions, some of which are novel in NMSC development. The further delineation of these loci should provide additional evidence of their significance and degree of involvement in NMSC tumourigenesis. The identification of the cancer-causing genes mapped to these loci will further demarcate the genetic mechanisms of BCC and SCC progression. An understanding of the events involved in skin cancer formation and progression should shed additional light on molecular targets for diagnostics, management and therapeutic treatment.

Dissertation (Ph.D.)--University of South Florida, 2007. / Includes vita. Includes bibliographical references. Also available online.

The Sli15-Ipl1-Bir1 chromosomal passenger complex is essential for proper kinetochore-microtubule attachment and spindle stability in the budding yeast Saccharomyces cerevisiae. Subcellular localization of this complex during anaphase is regulated by the Cdc14 protein phosphatase, which is kept inactive in the nucleolus until anaphase onset. I show here that the predominantly nucleolar ribosome biogenesis protein Utp7 is also present at kinetochores and is required for normal organization of kinetochore proteins and proper chromosome segregation. Utp7 associates with and regulates the localization of Sli15 and Cdc14. It prevents the abnormal localization of Sli15 on cytoplasmic microtubules, the premature concentration of Sli15 on the pre-anaphase spindle, and the premature nucleolar release of Cdc14 before anaphase onset. Utp7 regulates Sli15 localization not entirely through its effect on Cdc14. Furthermore, the mitotic exit block caused by Cdc14 inactivation is relieved partially by the simultaneous inactivation of Utp7. Thus, Utp7 is a multifunctional protein that plays essential roles in the vital cellular processes of ribosome biogenesis, chromosome segregation and cell cycle control. Protein phosphatase 1, Glc7 opposes in vivo functions of the Ipl1-Sli15-Bir1 kinase complex in budding yeast. I show here Scd5- a targeting subunit of Glc7 that regulates endocytosis/cortical actin organization and undergoes nuclear-cytoplasmic shuttling- is present at kinetochores. Ipl1 associates with both Glc7 and Scd5. The scd5-PP1[Delta]2 mutation, which disrupts the association between Glc7 and Scd5, also disrupts the association between Ipl1 and Scd5-Glc7 without affecting the kinetochore localization of these proteins. Genetic studies suggest that Scd5 may positively regulate both Glc7 phosphatase and the Ipl1 kinase complex. In accordance, Scd5 stimulates in vitro kinase activity of Ipl1. scd5-PP1[Delta]2 cells missegregate chromosomes severely due to several defects: i) at least one of sister kinetochores appears not attached to microtubule. ii) sister chromatids are persistently cohesed through anaphase. iii) Sli15 is hyperphosphorylated and less abundant on the anaphase spindle resulting in unstable mitotic spindle. These results together suggest that Scd5 functions in diverse processes that are essential for faithful chromosome segregation. How Scd5 coordinately regulates two apparently antagonistic enzymatic activities of Ipl1 and Glc7 remains to be determined. / text

Η αναζήτηση και επινόηση νέων προσεγγίσεων για την προγεννητική διάγνωση χρωμοσωμικών συνδρόμων, που να συνδυάζουν ταχύτητα, αξιοπιστία και ασφάλεια για την μητέρα και το έμβρυο, είναι πάντοτε επίκαιρη και επιτακτική, ιδιαίτερα στην εποχή μας, όπου η πρόοδος της μοριακής βιολογίας και η αποκρυπτογράφηση του ανθρώπινου γονιδιώματος, προσφέρουν νέα γνώση και εργαλεία για την προσπάθεια αυτή. Στην παρούσα εργασία τυποποιήθηκε η μεθοδολογία της ποσοτικής φθορίζουσας αλυσιδωτής αντίδρασης της πολυμεράσης (Quantitative Fluorescence Polymerase Chain Reaction, QF-PCR) σε συνδυασμό με τη συμβατική PCR για την ανίχνευση ανευπλοειδιών και φύλου σε δείγματα αμνιακών κυττάρων, σε βλαστομερίδια προεμβρύου και κυρίως σε ελεύθερο εμβρυϊκό DNA από την μητρική κυκλοφορία καθώς και σε ούρα της εγκύου, για την καθιέρωση μη επεμβατικής μεθοδολογίας προγεννητικής διάγνωσης. Είναι σαφές από τα αποτελέσματα της παρούσας ερευνητικής εργασίας ότι οι συγκεκριμένες μεθοδολογίες μπορούν να χρησιμοποιηθούν συμπληρωματικά στο συμβατικό χρωμοσωμικό έλεγχο και παράλληλα να αξιοποιηθούν όσον αφορά την ανάλυση του ελεύθερου εμβρυϊκού DNA στο πλάσμα της μητέρας για την ασφαλή διάγνωση του φύλου του εμβρύου στα πρώτα στάδια της κύησης. Επιπλέον, επινοήθηκαν πειράματα προσομοίωσης μητρικού πλάσματος με σκοπό τον προσδιορισμό του ποσοστού του εμβρυϊκού DNA στη μητρική κυκλοφορία σε όλη τη διάρκεια της κύησης. Τα αποτελέσματα έδειξαν ότι στα δείγματα μας το εμβρυϊκό DNA μπορεί να διαχωριστεί από το DNA της μητέρας, ανιχνεύοντας μοναδικά εμβρυϊκά αλληλόμορφα πολυμορφικών περιοχών STR (Short Tandem Repeats) πατρικής προέλευσης με QF-PCR. Αυτά τα αλληλόμορφα χρησιμοποιήθηκαν για τον υπολογισμό του ποσοστού του εμβρυϊκού DNA στο μητρικό πλάσμα. Έτσι βρέθηκε ότι σε φυσιολογικές κυήσεις, το εμβρυϊκό DNA είναι της τάξεως του 7% (διακύμανση 0-20%) του ολικού ελεύθερου DNA στη μητρική κυκλοφορία. Με βάση την ανάλυση των μοντέλων προσομοίωσης προσδιορίσθηκε με QF-PCR ο αριθμός των αντιγράφων των εμβρυϊκών χρωμοσωμάτων συγκρίνοντας τις αναλογίες των αλληλομόρφων δεικτών STR στα χρωμοσώματα 21, 18, 13, Χ και Υ. Τα αποτελέσματα έδειξαν ότι για φυσιολογικά έμβρυα και σε περιπτώσεις όπου το ποσοστό του εμβρυϊκού DNA στο μητρικό πλάσμα είναι ≥15%, ο λόγος των αναλογιών των αλληλομόρφων δύο δεικτών STR σε διαφορετικά χρωμοσώματα προσεγγίζει τη μονάδα. Η ανάλυση δειγμάτων μητρικού πλάσματος από φυσιολογικές κυήσεις και μετά από εμπλουτισμό τους στο ελεύθερο εμβρυϊκό DNA επιβεβαίωσε τα αποτελέσματα των μοντέλων προσομοίωσης. Αντίστοιχα μοντέλα προσομοίωσης δειγμάτων πλάσματος εγκύων με τρισωμικά έμβρυα για το χρωμόσωμα 21 έδειξαν ότι ο λόγος της αναλογίας των αλληλομόρφων ενός δείκτη STR σε ένα αυτοσωμικό χρωμόσωμα (π.χ. 18 ή 13) προς την αναλογία των αλληλομόρφων ενός δείκτη STR στο χρωμόσωμα 21, διαφέρει από τη μονάδα και εξαρτάται από την προέλευση, πατρική ή μητρική, του επιπλέον εμβρυϊκού χρωμοσώματος 21 στο δείγμα (0.5 έναντι 1.3 αντιστοίχως). Τα αποτελέσματα αυτά μπορούν, εφόσον επαληθευθούν σε ικανό αριθμό δειγμάτων να αξιοποιηθούν ως επιπλέον δείκτες προγεννητικού ελέγχου και ενδεχομένως να συμβάλλουν στην τυποποίηση αποτελεσματικής μεθοδολογίας μη επεμβατικής χρωμοσωμικής διάγνωσης. / The quest and devise of new approaches for the prenatal diagnosis of chromosomal syndromes that combine rapid analysis robustness and safety for mother and embryo are always in demand especially in the post-genome era with new tools and methods in our disposition. In the present study, the methodology of quantitative fluorescent polymerase chain reaction (QF-PCR) has been developed and standardized in conjunction with conventional PCR for the detection of aneuploidies and sex in amniotic cells, blastomeres and most importantly in free fetal DNA isolated from maternal peripheral blood and urine, for the establishment of non-invasive methods of prenatal diagnosis. It has become evident that the methodology we have followed can complement conventional prenatal chromosome analysis and in addition can be exploited for the analysis of fetal DNA in maternal plasma for fetal sex determination at the first stages of gestation. Moreover, simulation experiments have been devised in order to determine the percentage of fetal DNA in maternal circulation throughout pregnancy. Our results showed that free fetal DNA can be distinguished from the mother’s DNA in maternal plasma by identifying unique paternally inherited fetal polymorphisms, such as short tandem repeat (STR) alleles, with QF-PCR. These alleles were used to calculate the percentage of fetal DNA in maternal plasma. Fetal DNA was found to be present on an average of 7% (range 0-20%) of the total free DNA in maternal circulation, in normal pregnancies. QF-PCR analysis was also used to determine the copy number of fetal chromosomes by comparing the allelic ratios for chromosomes 21, 18, 13 X and Y. It appears that in informative cases where free fetal DNA is 15% or more and originates from normal embryos, the value of the allelic ratio of a STR marker on one chromosome divided by the value of the allelic ratio of another STR marker on a different chromosome is equal to 1. Analysis of DNA samples isolated from the plasma of pregnant women bearing normal embryos confirmed the results of the simulation models. Comparison of the above data with new analyses simulating DNA from the plasma of pregnant women carrying trisomic for chromosome 21 embryos have shown that the value of the allelic ratio of a STR marker on an autosomal chromosome (e.g. 18 or 13), divided by the allelic ratio of a STR marker on chromosome 21, is different from 1 and it depends on the origin, paternal or maternal, of the extra copy of chromosome 21 in the embryo, with values of 0.5 in paternal compared to 1.3 in maternal trisomies respectively. These results differentiate between normal and trisomic cases and after further evaluation may provide a new indication marker for prenatal diagnosis. In the long term, they may also provide the basis of a non-invasive procedure for early prenatal chromosomal analysis.

No description available.

Objective: Two chromosomal instability (CIN) pathways are described in glioblastoma multiforme (GBM), type 1 and type 2, which can be observed in up to 70% of the cases. Microsatellite instability (MSI) plays a pathogenic role in sporadic cancers such as colon, gastric and endometrial carcinomas with deficient mismatch repair (MMR). We aimed to perform a comprehensive analysis of the relationship between CIN and MSI mechanisms in sporadic glioblastomas. Methods: 129 GBMs were examined (109 newly diagnosed and 20 relapses) investigating MSI, immunohistochemical expression of MMR proteins as well as sequencing and promoter methylation of hMLH1. We characterized the molecular changes frequently correlated with CIN in MSI+ GBMs and compared them with 26 microsatellite-stable tumors. Results: Low-level MSI was observed in 11 of 129 (8.5%) cases and was higher in relapses than in primary GBMs (25 vs. 5.5%, p = 0.027). High-level MSI was not found in any case. A deficient expression of MLH1 and PMS2 without hMLH1 inactivation was observed only in one giant cell GBM. 55% of the MSI+ GBMs showed a profile which did not correspond to one of the known CIN pathways. An inverse association was observed between MSI and mutations of both p53 and PTEN. Conclusions: Our data suggest that CIN and MSI contribute to the genomic instability in GBMs via independent pathways. Since MSI was significantly more frequent in relapses, it might play a role in the malignant progression of GBM. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

La leucémie myéloïde chronique (LMC) est un modèle d’évolution tumorale dans les cancers humains. Le processus d’évolution de la LMC de la phase chronique (PC) à la phase blastique (PB) est caractérisé par un arrêt de différenciation et l’acquisition de la capacité d’autorenouvellement incontrôlé d’une cellule souche ou d’un progéniteur hématopoïétique. La LMC en PB est associée à la présence d’anomalies génétiques additionnelles à la fusion BCR-ABL1 qui résulte de la translocation chromosomique t(9;22). Contrairement aux patients en PC, les patients en PB de la LMC n’obtiennent pas une réponse moléculaire complète à long terme avec 1’Imatinib mesylate, un inhibiteur de la tyrosine kinase (ITK) BCR-ABL1. De plus, les ITKs de deuxième et troisième générations sont moins efficaces en PB de la LMC lorsque les cellules leucémiques ont acquis une résistance au traitement indépendante des mutations de BCR-ABL1. Les mécanismes moléculaires des voies de signalisation impliquées dans la progression de la LMC en PB ne sont pas entièrement élucidés. Le but de notre travail est de caractériser de nouvelles anomalies génétiques dans la PB de la LMC. Nous avons identifié en cytogénétique, quatre nouvelles translocations chromosomiques : t(1;21)(p36;q22), t(7;17)(p15;q22), t(8;17)(q11;q22) et t(2;12)(q31;p13) dans les cellules leucémiques de patients en PB de la LMC résistants au traitement. En utilisant des techniques d'hybridation in situ en fluorescence, de RT-PCR et de séquençage, nous avons délimité les régions à investiguer au niveau des points de cassure et identifié un réarrangement de plusieurs gènes codant pour des facteurs de transcription importants lors de l’hématopoïèse tels que RUNX1, ETV6, PRDM16 et HOXA. L’altération de ces gènes pourrait expliquer l’arrêt de différenciation et/ou l’acquisition de la capacité d’autorenouvellement caractéristiques de la LMC en PB. Nous avons identifié les fusions RUNX1-PRDM16, MSI2-HOXA, MSI2-SOX17 et ETV6-HOXD11, respectivement associées aux translocations chromosomiques t(1;21), t(7;17), t(8;17) et t(2;12). Ces fusions génèrent différents transcrits alternatifs qui maintiennent et altèrent le cadre ouvert de lecture. L’analyse des séquences des transcrits chimériques identifiés dans ce projet, incluant RUNX1-PRDM16, MSI2-HOXA9, MSI2-HOXA10, MSI2-HOXA11 et ETV6-HOXD11, nous a permis de prédire les domaines fonctionnels potentiellement présents au niveau des protéines chimériques prédites. Les transcrits de fusion qui respectent le cadre ouvert de lecture peuvent générer des domaines fonctionnels des deux partenaires. C’est le cas des deux transcrits identifiés pour la fusion RUNX1-PRDM16 où le domaine de liaison à l’ADN RHD (Runt homology domain) de RUNX1 est fusionné avec la quasi-totalité des domaines de PRDM16. Les transcrits de fusion qui ne respectent pas le cadre ouvert de lecture donnent des formes tronquées des transcrits RUNX1, MSI2 et ETV6. La juxtaposition des régions promotrices de ces derniers en 5’ de leurs partenaires entraîne l’activation de la forme courte oncogénique de PRDM16 dans la t(1;21) ou de différents gènes HOXA/D dans les t(7;17) et t(2;12), ainsi que l’expression aberrante d’un nouveau transcrit alternatif de SOX17 dans la t(8;17). Notre étude nous a permis d’identifier de nouveaux gènes de fusion et/ou une activation de gènes qui pourraient coopérer avec la fusion BCR-ABL1 dans la progression de la LMC et être impliqués dans la résistance au traitement de la LMC en phase avancée. La caractérisation des événements génétiques associés à la transformation blastique de la LMC est essentielle pour l’investigation des voies moléculaires impliquées dans cette phase de la maladie. Investiguer la résistance au traitement de ces patients pourrait aussi contribuer à identifier de nouvelles cibles thérapeutiques dans cette leucémie. / Chronic myeloid leukemia (CML) is a model of tumor evolution in human cancer. The evolution process of CML from the chronic phase (CP) to the blastic phase (BP) is characterized by a blockade of differentiation and acquisition of uncontrolled self-renewal capacity by hematopoietic stem or progenitor cells. CML-BP is associated with the presence of other genetic abnormalities in addition to the BCR-ABL1 fusion which results from chromosomal translocation t(9;22). Unlike patients in the CP, patients with CML-BP do not achieve a long-term complete molecular response to Imatinib mesylate, an inhibitor targeting the BCR-ABL1 tyrosine kinase (TK). Moreover, second and third generation TK inhibitors are less effective in CML-BP when leukemic cells have acquired a therapeutic resistance independent of BCR-ABL1 mutations. The molecular mechanisms of the signaling pathways responsible for CML progression from CP to BP are poorly understood. The aim of our project is to characterize novel genetic alterations in the BP of CML. We have identified by cytogenetics, four novel chromosomal translocations: t(1;21)(p36;q22), t(7;17)(p15;q22), t(8;17)(q11;q22) and t(2;12)(q31;p13) in leukemic cells of patients with CML-BP resistant to therapy. Using fluorescence in situ hybridization, RT-PCR and sequencing techniques, we have mapped chromosomal translocation breakpoints and identified rearranged genes encoding transcription factors which are key regulators of hematopoiesis, such as RUNX1, ETV6, PRDM16 and HOXA. The disruption of these genes could explain the differentiation blockade and/or uncontrolled self-renewal associated with the CML-BP. We identified RUNX1-PRDM16, MSI2-HOXA, MSI2-SOX17 and ETV6-HOXD11 fusions created by chromosomal translocations t(1;21), t(7;17), t(8;17) and t(2;12) respectively. These fusions generate different alternative transcripts that both maintain and alter the open reading frame. Sequence analysis of chimeric transcripts identified in this project, including RUNX1-PRDM16, MSI2-HOXA9, MSI2-HOXA10, MSI2-HOXA11 and ETV6-HOXD11, allowed us to predict potential functional domains present in putative chimeric proteins. In-frame fusion transcripts can generate functional domains from both fusion partners. For example, in two RUNX1-PRDM16 transcripts, the RUNX1 DNA binding domain RHD (Runt homology domain) is fused to the majority of PRDM16 domains. Out-of-frame fusion transcripts resulted in truncated forms of RUNX1, MSI2 and ETV6. The juxtaposition of promoter regions of these genes to the 5’ part of their partners resulted in the activation of the oncogenic short form of PRDM16 in the t(1;21) or of different HOXA/D genes in t(7;17) and t(2;12), and in the aberrant expression of a novel alternative SOX17 transcript in the t(8;17). Our study allowed us to identify novel fusion genes and/or activation of genes that potentially cooperate with BCR-ABL1 fusion in the progression of CML and contribute to treatment resistance of this disease. The characterization of genetic events related to the blastic transformation of CML is an important step in the investigation of molecular pathways involved in this stage of the disease. Understanding treatment resistance of these patients might help to identify new therapeutic targets in this leukemia.

Uncovering the chromosomal abnormalities associated with human malignancy can provide significant insights into the molecular basis of tumorigenesis, as well as identifying potential targets for therapy. The present study set out to examine the genetic characteristics of t(2;7)(p11-12;q21-22) translocations arising in conjunction with chronic B-cell neoplasia. Using long-range PCR, a t(2;7) was initially mapped in an individual presenting with the preclinical entity CD5- monoclonal B-cell lymphocytosis. This revealed a breakpoint at 2p11.2 localized to the recombination signal of the immunoglobulin kappa (IGK) variable gene IGKV3-15, and a breakpoint at 7q21.2 located 520 bp upstream of cyclin dependent kinase 6 (CDK6). The same approach was subsequently employed to elucidate near-identical t(2;7) breakpoints in 4 additional cases presenting with chronic lymphocytic leukemia or indolent non-Hodgkin lymphomas. The remarkable consistency of these translocations implicates the dysregulation of CDK6 via translocation to IGK as a recurrent pathomechanism during the emergence of B-cell lymphoproliferative disorders.

Uncovering the chromosomal abnormalities associated with human malignancy can provide significant insights into the molecular basis of tumorigenesis, as well as identifying potential targets for therapy. The present study set out to examine the genetic characteristics of t(2;7)(p11-12;q21-22) translocations arising in conjunction with chronic B-cell neoplasia. Using long-range PCR, a t(2;7) was initially mapped in an individual presenting with the preclinical entity CD5- monoclonal B-cell lymphocytosis. This revealed a breakpoint at 2p11.2 localized to the recombination signal of the immunoglobulin kappa (IGK) variable gene IGKV3-15, and a breakpoint at 7q21.2 located 520 bp upstream of cyclin dependent kinase 6 (CDK6). The same approach was subsequently employed to elucidate near-identical t(2;7) breakpoints in 4 additional cases presenting with chronic lymphocytic leukemia or indolent non-Hodgkin lymphomas. The remarkable consistency of these translocations implicates the dysregulation of CDK6 via translocation to IGK as a recurrent pathomechanism during the emergence of B-cell lymphoproliferative disorders.