Segmental amplification of MLL gene associated with high expression of AURKA and AURKB genes in a case of acute monoblastic leukemia with complex karyotype

We report a case of acute monoblastic leukemia showing a jumping translocation with the MLL gene in a 17-year-old male. Classic cytogenetic and spectral karyotyping revealed a complex karyotype, and fluorescence in situ hybridization (FISH) demonstrated amplification of the MLL gene followed by translocation to chromosomes 15q, 17q, and 19q. In addition, molecular analyses showed a high expression of AURKA and AURKB genes. It is already known that overexpression of Aurora kinases is associated with chromosomal instability and poor prognosis. The formation of jumping translocations is a rare cytogenetic event and there is evidence pointing toward preferential involvement of the heterochromatin region of donor chromosomes and the telomere ends of recipient chromosomes. Jumping translocation with the MLL gene rearrangement is an uncommon phenomenon reported in leukemia cytogenetics. (C) 2010 Elsevier Inc. All rights reserved.

Spatial variation in the strength of mutualism between a jumping spider and a terrestrial bromeliad: Evidence from the stable isotope N-15

Psecas chapoda, a neotropical jumping spider strictly associated with the terrestrial bromeliad Bromelia balansae in cerrados and semi-deciduous forests in South America, effectively contributes to plant nutrition and growth. In this study, our goal was to investigate if spider density caused spatial variations in the strength of this spider-plant mutualism. We found a positive significant relationship between spider density and delta N-15 values for bromeliad leaves in different forest fragments. Open grassland Bromeliads were associated with spiders and had higher delta N-15 values compared to forest bromeliads. Although forest bromeliads had no association with spiders their total N concentrations were higher. These results suggest that bromeliad nutrition is likely more litter-based in forests and more spider-based in open grasslands. This study is one of the few to show nutrient provisioning and conditionality in a spider-plant system. (c) 2008 Elsevier Masson SAS. All rights reserved.

Manipulation of rest period length induces different causes of fatigue in vertical jumping

The aim of this study was to directly compare the causes of fatigue after a short- and a long-rest interval between consecutive stretch-shortening cycle exercises. Eleven healthy males jumped with different resting period lengths (short = 6.1 +/- 1 s, long = 8.6 +/- 0.9 s), performing countermovement jumps at 95% of their maximal jump height until they were unable to sustain the target height. After short- and long-rest, the maximal voluntary isometric contraction knee extension torque decreased (-7%; p = 0.04), comparing to values obtained before exercise protocols. No change was seen from pre- to post-exercise, for either short- or long-rest, in biceps femoris coactivation (-1%; p = 0.95), peak-to-peak amplitude (1%; p = 0.95) and duration (-8%; p = 0.92) of the compound muscle action potential of the vastus lateralis. Evoked peak twitch torque reduced after both exercise protocols (short = -26%, long = -32%; p = 0.003) indicating peripheral fatigue. However, central fatigue occurred only after short-rest evidenced by a reduction in voluntary activation of the quadriceps muscle (-14%; p = 0.013) measured using the interpolated twitch technique. In conclusion, after Stretch-shortening cycle exercise using short rest period length, the cause of fatigue was central and peripheral, while after using long rest period length, the cause of fatigue was peripheral.

The influence of resting period length on jumping performance

Pereira, G, Almeida, AG, Rodacki, ALF, Ugrinowitsch, C, Fowler, NE, Kokubun, E. The influence of resting period length on jumping performance. J Strength Cond Res 22: 1259-1264, 2008-The purpose of this study was to determine a resting interval between countermovement jumps (i.e., volleyball spikes) that allows the maintenance of maximal jumping performance. Ten male volleyball players (1.85 +/- 0.05 m, 77.2 +/- 10.6 kg, 21.6 +/- 5.3 years) performed 6 experimental jumping sessions. In the first and sixth sessions, maximal countermovement jump height was measured, followed by submaximal countermovement jumps to the point of volitional fatigue. The number of countermovement jumps was used as a reference to test the effect of rest period between volleyball spikes. From the second to fifth experimental sessions, 30 maximal volleyball spikes were performed with different resting periods (i.e., 8, 14, 17, and 20 seconds) followed by countermovement jumps. Between the 15th and 30th spikes, the blood lactate concentration and heart rate were measured. Because the performance on the first and sixth sessions was the same, no training effects were noticed. During the 8-second resting interval set, the lactate concentration increased significantly between the 15th and 30th spikes (i.e., from 3.37 +/- 1.16 mmol to 4.94 +/- 1.49 mmol); the number of countermovement jumps decreased significantly after spikes compared to those performed without a previous effort (i.e., from 23 +/- 7 jumps to 17 +/- 9 jumps); and these variables were significantly correlated (r = -0.7). On the other hand, the lactate concentration and number of countermovement jumps were stable across the other resting intervals, without a heart rate steady state. The results indicate that an adequate resting period between spikes allowed participants to achieve a lactate steady state in which the performance was maintained during the exercise. These findings show that resting intervals between 14 and 17 seconds, typical during volleyball matches, are indicated to use in volleyball spike drills due to their capacity to maintain maximal jumping performance.

Translocations t(X;14)(q28;q11) and t(Y;14)(q12;q11) in T-cell prolymphocytic leukemia

P>We report a case of T-cell prolymphocytic leukemia (T-PLL) in a 41-year-old male. Classical cytogenetic, spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) studies of a blood sample obtained at diagnosis revealed the co-existence of t(X;14)(q28;q11), t(Y;14)(q12;q11) and a ring chromosome derivated from i(8)(q10). Immunophenotypic studies revealed involvement of T-cell lineage, with proliferation of CD4(-) CD8(+). The co-existence of two translocations involving both sex chromosomes in a case of T-PLL is rare. Chromosomal instability associated with the disease progression may have allowed the emergence of cell clones with translocations involving the sex chromosomes and the ring chromosome observed.

The role of complex chromosome translocations in leukemia

Resumo A tumorigénese é um processo de transformação celular que se desenrola tipicamente em várias etapas. Os diferentes níveis de evolução tumoral resultam da acumulação sucessiva de mutações genéticas numa célula normal que lhe conferem uma vantagem selectiva no respectivo meio tecidular. As mutações podem manifestar-se sob a forma de alterações nucleotídicas pontuais ao nível da sequência de DNA, levando a uma desregulação da função proteíca ou à formação de proteínas não-funcionais, ou através de alterações cromossómicas numéricas ou estruturais. Na leucemia, por exemplo, os genes híbridos que resultam de translocações cromossómicas desempenham um importante papel no processo tumorigénico. Estes genes são transcritos sob a forma de um RNA mensageiro de fusão, o qual é traduzido numa proteína híbrida com função oncogénica. Frequentemente, os subtipos de doença leucémica estão associados com translocações cromossómicas que envolvem 2 pontos de quebra recorrentes e específicos. É disto exemplo a leucemia mielóide crónica, em que uma translocação recíproca entre os cromossomas 9 e 22 conduz à formação de um gene de fusão BCR-ABL1. Em diferentes subtipos de doença, existe também uma pequena proporção de casos que apresenta translocações cromossómicas complexas, que envolvem um ou mais pontos de quebra adicionais em outras localizações genómicas além das que estão implicadas na formação dos genes de fusão. Por vezes, os pontos de quebra estão também associados a delecções extensas de material genético que se pensa terem uma função importante na tumorigénese. No entanto, o papel destas regiões genómicas no desenvolvimento tumoral não tem sido um motivo recorrente de estudo. Neste contexto, o objectivo desta dissertação foi o de determinar o potencial papel tumorigénico de alterações génicas adicionais ocorridas nos pontos de quebra de translocações cromossómicas complexas. Para a prossecução do objectivo proposto, foram estudados 5 rearranjos cromossómicos distintos associados com diferentes tipos de doença hematológica maligna, nomeadamente a leucemia linfoblástica aguda de células B (2 casos), leucemia mielóide aguda, neoplasma mieloproliferativo e síndrome mielodisplásico/neoplasma ieloproliferativo, não classificável. O mapeamento dos pontos de quebra foi efectuado utilizando a hibridação fluorescente in situ e diferentes metodologias de biologia molecular, tendo como base a informação inicial da análise citogenética. Em casos seleccionados, o papel dos novos genes candidatos foi avaliado in vitro utilizando modelos de linhas celulares, nomeadamente no que respeita às funções de controlo da proliferação celular e de regulação transcricional. De entre os 5 casos estudados, quatro deles evidenciaram translocações complexas envolvendo 3 cromossomas, nomeadamente t(12;21;5)(p13;q22;q13), t(12;6;15)(p13;p24~25;q22), t(9;11;19)(p22;q23;p13) e t(X;20;16)(p11;q13;q23). No caso remanescente, foi observada uma translocação dicêntrica dic(9;12)(p11;p11) acompanhada de delecções extensas em ambos os pontos de quebra. Nos casos com t(12;21;5) e t(9;11;19) as translocações estavam associadas com a presença de genes de fusão recorrentes, nomeadamente TV6(12p13)-RUNX1(21q22) e TLL(11q23)-MLLT3(9p22), indicando que se tratavam de rearranjos complexos das translocações t(12;21) e t(9;11) associadas com a leucemia linfoblástica aguda de células B e a leucemia mielóide aguda, respectivamente. O papel dos pontos de quebra adicionais foi estudado em detalhe no caso com t(9;11;19). Através da metodologia de long distance inverse-polymerase chain reaction, foram identificados os pontos de quebra na sequência de DNA dos 3 cromossomas envolvidos na translocação. Além dos pontos de quebra nos genes MLL e MLLT3, foi observado que o local de quebra no cromossoma 19 interrompeu a sequência de um novo gene, designado CCDC94,conduzindo à sua haplo-insuficiência nas células com t(9;11;19). Através de ensaios de reverse transcription-polymerase chain reaction verificámos que o gene CCDC94 é expresso ubiquitariamente em tecidos humanos normais. A análise informática da sequência prevista da proteína CCDC94 indicou uma elevada identidade de aminoácidos com a proteína cwf16, envolvida na regulação do ciclo celular da levedura Schizosaccharomyces pombe. Através da clonagem do DNA complementar de CCDC94 em vectores de expressão, e após a transfecção destes em culturas de linhas celulares in vitro, observámos que este gene codifica uma proteína de localização exclusivamente nuclear. A expressão ectópica da proteína CCDC94 diminuiu a progressão do ciclo celular e a proliferação das células em cultura. Inversamente, a supressão do transcrito do gene CCDC94 através de interferência de RNA conduziu a um aumento significativo da proliferação celular, confirmando que CCDC94 regula negativamente a proliferação e a progressão do ciclo celular. Estes resultados mostram que os pontos de quebra adicionais, presentes em translocações cromossómicas complexas em leucemia, podem resultar na haplo-insuficiência de genes controladores dos mecanismos proliferativos, cooperando desta forma com a acção das proteínas de fusão para proporcionar ao clone leucémico uma proliferação celular descontrolada. Nos restantes 3 casos estudados não foram identificados genes de fusão. Ao invés, todos aqueles apresentaram delecções de extensão variável associadas com os pontos de quebra cromossómicos. No caso com t(12;6;15), identificámos uma delecção de 1.2 megabases de DNA na banda 12p13 que resultou na eliminação de 9 genes incluindo ETV6 e CDKN1B. O gene ETV6 codifica um factor de transcrição que é essencial para a formação das diferentes linhagens hematopoiéticas na medula óssea, enquanto CDKN1B é traduzido numa proteína responsável por bloquear a entrada das células na fase G1 do ciclo celular e,consequentemente, por travar a proliferação celular. Neste contexto, os resultados obtidos indicam que a perda simultânea de ETV6 e de CDKN1B, através de uma translocação cromossómica complexa, constituiu uma acção cooperativa na leucemogénese. A mesma noção pode aplicar-se ao caso com dic(9;12), no qual pelo menos 2 genes que codificam para factores de transcrição importantes na linhagem hematopoiética, PAX5 no cromossoma 9 e ETV6 no cromossoma 12, estavam deleccionados como resultado do rearranjo cromossómico. Dado que o factor de transcrição PAX5 regula negativamente a expressão do gene FLT3, que desempenha uma função pró-proliferativa, é expectável que a haplo-insuficiência de PAX5 no caso com dic(9;12) terá tido como consequência uma elevação dos níveis de expressão de FLT3, contribuindo deste modo para uma proliferação celular aumentada. A t(X;20;16) foi identificada num doente com trombocitémia essencial (TE), uma doença que está intimamente relacionada com alterações de vias intracelulares reguladas por citocinas. Neste caso, através da utilização de um array genómico, identificámos a presença de pequenas delecções associadas com os pontos de quebra nos cromossomas 16 e 20. No cromossoma 16 apenas um gene, MAF, estava deleccionado, enquanto no cromossoma 20 a delecção tinha abrangido 3 genes. Dos genes deleccionados, dois deles, NFATC2 (20q13) e MAF (16q23), codificam proteínas que operam como reguladores transcricionais de citocinas hematopoiéticas. Dado que NFATC2 se localiza numa região que constitui um alvo frequente de delecções em neoplasmas ieloproliferativos, incluindo a trombocitémia essencial,efectuámos um estudo detalhado do papel deste gene na proliferação megacariocítica e na regulação da expressão de uma citocina hematopoiética (GM-CSF), implicada na maturação das diferentes linhagens mielóides. Utilizando um modelo de linha celular de trombocitémia essencial, verificámos que a supressão do transcrito do gene NFATC2 in vitro, por interferência de RNA, estava associada com um aumento da proliferação celular. Em concordância, o bloqueio da activação da proteína NFATC2 através de um inibidor específico da sua interacção com a calcineurina, conduziu a um aumento da proliferação celular in vitro. Utilizando a PCR quantitativa em tempo real, detectou-se um aumento da produção do RNA de GM-CSF em ambos os ensaios celulares, indicando que o factor de transcrição NFATC2 pode regular negativamente a expressão de GM-CSF em células de trombocitémia essencial. No geral, estes resultados mostram que a redução dos níveis fisiológicos do transcrito NFATC2, ou a redução da respectiva actividade proteica, estão relacionados com a proliferação de megacariocitos através do aumento da produção de GM-CSF. De acordo com estes resultados, verificámos que as células dos doentes com TE apresentam níveis mais baixos do transcrito NFATC2 do que a população normal. Dado que o factor de transcrição MAF desempenha igualmente um papel como regular transcricional de citocinas, é plausível que a haplo-insuficiência dos genes NFATC2 e MAF, resultante do rearranjo cromossómico complexo t(X;20;16), teve um efeito cooperativo importante na patogénese da trombocitémia essencial através da alteração do padrão normal de expressão das citocinas hematopoiéticas. Em síntese, efectuámos nesta dissertação um estudo citogenético de 4 translocações cromossómicas complexas incluindo t(12;21;5), t(12;6;15), t(9;11;19) e t(X;20;16), e de uma translocação dicêntrica dic(9;12), associadas com diferentes neoplasmas hematológicos. Em casos seleccionados efectuámos também um estudo molecular detalhado das regiões dos pontos de quebra. Esta análise permitiu-nos identificar 2 genes, CCDC94 no cromossoma 19 e NFATC2 no cromossoma 20, cuja haplo-insuficiência pode promover o aumento da proliferação celular das células leucémicas. A partir destes estudos podem ser retiradas 2 noções principais: (i) Os pontos de quebra adicionais, que ocorrem em translocações complexas associadas com a formação de genes de fusão, podem ter como consequência a desregulação de genes controladores da proliferação celular (e.g., CCDC94); (ii) As translocações complexas caracterizadas pela ausência de genes de fusão recorrentes poderão estar preferencialmente associadas com a presença de delecções, envolvendo um ou mais genes, nos pontos de quebra; nestas situações, serão necessários pelo menos 2 genes com funções celulares semelhantes (e.g., NFATC2 e MAF) ou complementares (e.g., ETV6 e CDKN1B) para, quando deleccionados, promoverem de forma cooperativa a leucemogénese. Nestes termos, o modelo de alterações genéticas sequenciais que caracteriza o desenvolvimento do cancro pode ser substituído por um modelo em que vários genes-alvo são simultaneamente desregulados pela formação de uma translocação cromossómica complexa, evitando deste modo a necessidade de ocorrência de alterações genéticas subsequentes.----------------------ABSTRACT: Tumourigenesis is a multistep process which results from the accumulation of successive genetic mutations in a normal cell. In leukemia for instance, recurrent translocations play a part in this process by generating fusion genes which lead to the production of hybrid proteins with an oncogenic role. However, a minor subset of chromosomal translocations referred to as complex or variant involves extra breakpoints at variable genome locations in addition to those implicated in the formation of fusion genes. We aimed to describe in this work the role, if any, of genes located at extra breakpoint locations or which are affected by breakpoint-adjacent deletions through the study of 5 leukemia patients.Two of the patients presented with TV6(12p13)-RUNX1(21q22) and MLL(11q23)- MLLT3(9p22) fusion genes as a result of a t(12;21;5) and a t(9;11;19), respectively. Detailed molecular characterization of the extra breakpoint at chromosome 19 in the latter case revealed that a novel ubiquitously expressed gene, CCDC94, with a potential role in cell cycle regulation, was disrupted by the breakpoint. We demonstrated using in vitro cellular assays that this gene codifies for a nuclear protein which negatively regulates cell cycle progression. These data shows that extra breakpoint locations of complex translocations may result in haplo-insufficiency of critical proliferation genes, thereby cooperating with the generation of hybrid proteins to provide unrestrained cell proliferation. In the other 3 patients there were reakpoint-associated deletions which precluded the formation of putative fusion genes. In a case with a t(12;6;15) we characterized a deletion at 12p13 which eliminated ETV6 and 8 other genes including CDKN1B. These findings indicate that concomitant loss of ETV6 and CDKN1B, which encodes a cyclin-dependent kinase inhibitor responsible for blocking entry of cells into the G1 phase of the cell cycle, acted cooperatively to promote leukemogenic proliferation. The same notion applied to a case with a dic(9;12) in which 2 genes encoding hematopoietic transcription factors - ETV6 and PAX5 (9p13)- were deleted as a result of breakpoint-adjacent deletions. Similarly, we found that 2 transcription factor genes involved in the regulation of cytokine expression, NFATC2 (20q13) and MAF (16q23), were involved in deletions contiguous to the breakpoints in a patient with a t(X;20;16). In vitro suppression of NFATC2 mRNA or inhibiton of NFATC2 protein activity enhanced cell proliferation as a result of an increase in the production of a myeloid-lineage stimulating hematopoietic cytokine, GM-CSF. These results suggest that haplo-insufficiency of NFATC2 and MAF genes had a cooperative effect in inducing cell proliferation as a result of a disregulation of cytokine production. Two main conclusions may be drawn from our studies: (i) In complex translocations associated with the production of fusion genes, additional breakpoints may cooperate in tumourigenesis by targeting genes that control cell proliferation; (ii) In complex translocations associated with small breakpoint-adjacent deletions, at least 2 genes with similar or complementary functions need to be deregulated to promote tumourigenesis.

Automatic measurement of key ski jumping phases and temporal events with a wearable system.

We propose a new method, based on inertial sensors, to automatically measure at high frequency the durations of the main phases of ski jumping (i.e. take-off release, take-off, and early flight). The kinematics of the ski jumping movement were recorded by four inertial sensors, attached to the thigh and shank of junior athletes, for 40 jumps performed during indoor conditions and 36 jumps in field conditions. An algorithm was designed to detect temporal events from the recorded signals and to estimate the duration of each phase. These durations were evaluated against a reference camera-based motion capture system and by trainers conducting video observations. The precision for the take-off release and take-off durations (indoor < 39 ms, outdoor = 27 ms) can be considered technically valid for performance assessment. The errors for early flight duration (indoor = 22 ms, outdoor = 119 ms) were comparable to the trainers' variability and should be interpreted with caution. No significant changes in the error were noted between indoor and outdoor conditions, and individual jumping technique did not influence the error of take-off release and take-off. Therefore, the proposed system can provide valuable information for performance evaluation of ski jumpers during training sessions.

Measurement of the dynamics in ski jumping using a wearable inertial sensor-based system.

Abstract Dynamics is a central aspect of ski jumping, particularly during take-off and stable flight. Currently, measurement systems able to measure ski jumping dynamics (e.g. 3D cameras, force plates) are complex and only available in few research centres worldwide. This study proposes a method to determine dynamics using a wearable inertial sensor-based system which can be used routinely on any ski jumping hill. The system automatically calculates characteristic dynamic parameters during take-off (position and velocity of the centre of mass perpendicular to the table, force acting on the centre of mass perpendicular to the table and somersault angular velocity) and stable flight (total aerodynamic force). Furthermore, the acceleration of the ski perpendicular to the table was quantified to characterise the skis lift at take-off. The system was tested with two groups of 11 athletes with different jump distances. The force acting on the centre of mass, acceleration of the ski perpendicular to the table, somersault angular velocity and total aerodynamic force were different between groups and correlated with the jump distances. Furthermore, all dynamic parameters were within the range of prior studies based on stationary measurement systems, except for the centre of mass mean force which was slightly lower.

Characterization of lower-limbs inter-segment coordination during the take-off extension in ski jumping.

Take-off, the most important phase in ski jumping, has been primarily studied in terms of spatio-temporal parameters; little is known about its motor control aspects. This study aims to assess the inter-segment coordination of the shank-thigh and thigh-sacrum pairs using the continuous relative phase (CRP). In total 87 jumps were recorded from 33 athletes with an inertial sensor-based system. The CRP curves indicated that the thighs lead the shanks during the first part of take-off extension and that the shanks rotated faster at the take-off extension end. The thighs and sacrum first rotated synchronously, with the sacrum then taking lead, with finally the thighs rotating faster. Five characteristic features were extracted from the CRP and their relationship with jump length was tested. Three features of the shank-thigh pair and one of the thigh-sacrum pair reported a significant association with jump length. It was observed that athletes who achieved longer jumps had their thighs leading their shanks during a longer time, with these athletes also having a more symmetric movement between thighs and sacrum. This study shows that inter-segment coordination during the take-off extension is related to performance and further studies are necessary to contrast its importance with other ski jumping aspects.

Reciprocal Translocations in Cattle: frequency estimation

Chromosomal anomalies, like Robertsonian and reciprocal translocations represent a big problem in cattle breeding as their presence induces, in the carrier subjects, a well documented fertility reduction. In cattle reciprocal translocations (RCPs, a chromosome abnormality caused by an exchange of material between nonhomologous chromosomes) are considered rare as to date only 19 reciprocal translocations have been described. In cattle it is common knowledge that the Robertsonian translocations represent the most common cytogenetic anomalies, and this is probably due to the existence of the endemic 1;29 Robertsonian translocation. However, these considerations are based on data obtained using techniques that are unable to identify all reciprocal translocations and thus their frequency is clearly underestimated. The purpose of this work is to provide a first realistic estimate of the impact of RCPs in the cattle population studied, trying to eliminate the factors which have caused an underestimation of their frequency so far. We performed this work using a mathematical as well as a simulation approach and, as biological data, we considered the cytogenetic results obtained in the last 15 years. The results obtained show that only 16% of reciprocal translocations can be detected using simple Giemsa techniques and consequently they could be present in no less than 0,14% of cattle subjects, a frequency five times higher than that shown by de novo Robertsonian translocations. This data is useful to open a debate about the need to introduce a more efficient method to identify RCP in cattle.

Jumping Jack Flash.

A 38-year-old woman presented with blurred vision and "jumping" of the right eye for 7 months. Magnetic resonance imaging of the head was normal. Intermittent intorsion of the right eye was noted on examination, consistent with superior oblique myokymia. She was initially treated with carbamazepine but stopped after becoming light-headed. The diagnosis and treatment of superior oblique myokymia are discussed.

t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders.

Through a combined approach integrating RNA-Seq, SNP-array, FISH and PCR techniques, we identified two novel t(15;21) translocations leading to the inactivation of RUNX1 and its partners SIN3A and TCF12. One is a complex t(15;21)(q24;q22), with both breakpoints mapped at the nucleotide level, joining RUNX1 to SIN3A and UBL7-AS1 in a patient with myelodysplasia. The other is a recurrent t(15;21)(q21;q22), juxtaposing RUNX1 and TCF12, with an opposite transcriptional orientation, in three myeloid leukemia cases. Since our transcriptome analysis indicated a significant number of differentially expressed genes associated with both translocations, we speculate an important pathogenetic role for these alterations involving RUNX1.

Caractérisation clinique et moléculaire de nouvelles translocations chromosomiques ciblant le gène RUNX1 dans les leucémies aiguës de l’adulte

La leucémie aiguë myéloïde est une hémopathie maligne génétiquement hétérogène caractérisée par de fréquents réarrangements impliquant la bande chromosomique 21q22 et le gène RUNX1. Dans ce groupe d’anomalies, les translocations t(8;21)(q22;q22) et t(3;21)(q26;q22), associées respectivement à un pronostic favorable et défavorable, sont les mieux étudiées. Or, plus de la moitié des réarrangements ciblant RUNX1 ne sont toujours pas caractérisés au niveau clinique et moléculaire. Les principaux objectifs de cette thèse sont de caractériser quatre nouvelles translocations ciblant RUNX1 et d’étudier la dérégulation transcriptionnelle associée à ces anomalies au niveau de cibles plus spécifiques ayant un rôle dans l’auto-renouvellement ou dans la différenciation hématopoïétique. À l’aide des techniques de cytogénétique et de biologie moléculaire, deux nouveaux partenaires de RUNX1, soit CLCA2 et SV2B, ont été identifiés au sein des t(1;21)(p22.3;q22) et t(15;21)(q26.1;q22) et la récurrence des partenaires USP42 et TRPS1 a été démontrée suite à l’étude des t(7;21)(p22.1;q22) et t(8;21)(q23.3;q22). Ce travail a permis de confirmer l’existence de divers modes de dérégulation de RUNX1 dans les leucémies aiguës. L’expression présumée de protéines chimériques et/ou d’isoformes tronquées de RUNX1, un dosage aberrant des transcrits de RUNX1 et la surexpression des gènes partenaires sont des conséquences révélées par l’étude de ces fusions. Le séquençage et l’analyse des jonctions génomiques des fusions récurrentes RUNX1-USP42/USP42-RUNX1 et RUNX1-TRPS1/TRPS1-RUNX1 ont démontré la présence de signatures moléculaires caractéristiques du mode de recombinaison non-homologue de type NHEJ. En raison de la structure et de la composition différente des jonctions, l’implication de composantes distinctes du mécanisme NHEJ a été proposée. Enfin, des analyses par PCR quantitative en temps réel nous ont permis de démontrer l’existence de cibles de dérégulation partagées par les fusions récurrentes et plus rares de RUNX1. Nous avons démontré que CEBPA est moins exprimé dans la majorité des spécimens étudiés présentant une fusion de RUNX1 par rapport aux spécimens avec un caryotype normal alors que JUP, une composante effectrice de la voie Wnt, est plutôt surexprimé. Malgré l’activation transcriptionnelle de JUP dans l’ensemble de ces spécimens, certaines cibles de la voie Wnt telles que CCND1 et MYC sont différemment exprimées dans ces cellules, appuyant l’hétérogénéité décrite dans ce groupe de leucémies. Malgré l’implication de partenaires variés, nos données d’expression démontrent que les chimères et les protéines tronquées de RUNX1 partagent des cibles communes d’activation et de répression transcriptionnelle et établissent, pour la première fois, des évidences moléculaires suggérant l’existence de similitudes entre la fusion récurrente RUNX1-RUNX1T1 et quatre fusions plus rares de RUNX1. Puisque des rechutes surviennent fréquemment dans ce groupe génétique, l’inhibition de JUP pourrait être une option thérapeutique intéressante et ceci est appuyé par les bénéfices observés lors de l’inhibition de la voie Wnt dans d’autres groupes génétiques de leucémies aiguës.