t(12;13)(p13;q12) ETV6/FLT3

Review on t(12;13)(p13;q12) ETV6/FLT3 , with data on DNA, on the protein encoded, and where the gene is implicated

t(11;22)(q13;q13) HRASLS5/PHF21B

Review on t(11;22)(q13;q13), with data on clinics, and the genes involved

Using Bacterial Artificial Chromosomes in Leukemia Research: The Experience at the University Cytogenetics Laboratory in Brest, France

The development of the bacterial artificial chromosome (BAC) system was driven in part by the human genome project in order to construct genomic DNA libraries and physical maps for genomic sequencing. The availability of BAC clones has become a valuable tool for identifying cancer genes. We report here our experience in identifying genes located at breakpoints of chromosomal rearrangements and in defining the size and boundaries of deletions in hematological diseases. The methodology used in our laboratory consists of a three-step approach using conventional cytogenetics followed by FISH with commercial probes, then BAC clones. One limitation to the BAC system is that it can only accommodate inserts of up to 300 kb. As a consequence, analyzing the extent of deletions requires a large amount of material. Array comparative genomic hybridization (array-CGH) using a BAC/PAC system can be an alternative. However, this technique has limitations also, and it cannot be used to identify candidate genes at breakpoints of chromosomal rearrangements such as translocations, insertions, and inversions

inv(3)(q21q26) RPN1/MECOM

review on inv(3)(q21q26) RPN1/MECO

ETV6-RUNX1 and RUNX1 directly regulate RAG1 expression: one more step in the understanding of childhood B-cell acute lymphoblastic leukemia leukemogenesis.

Funder: Société Française de Biochimie et Biologie Moléculaire ; French Research MinistryFunder: Cancéropole Grand Ouest ; Région Bretagne ; Société Française d’HématologieFunder: Ligue Régionale contre le cancer ;ETV6-RUNX1 and RUNX1 directly promote RAG1 expression. ETV6-RUNX1 and RUNX1 preferentially bind to the −1200 bp enhancer of RAG1 and the −80 bp promoter of RAG1 gene respectively, and compete for these bindings. ETV6-RUNX1 and RUNX1 induce an excessive RAG recombinase activity. ETV6-RUNX1 participates directly in two events of the multi-hit ALL leukemogenesis: as an initiating event and as an activator of RAG1 expression

Dissection cytogénétique des anomalies du chromosome 5 et du chromosome 20 dans les syndromes myélodysplasiques

Les syndromes myélodysplasiques (SMD) sont des hémopathies malignes chroniques d origine myéloïde caractérisées par une hétérogénéité clinique et biologique. Les anomalies chromosomiques, principalement déséquilibrées, sont présentes chez 50 % des patients atteints de SMD après étude en cytogénétique. Parmi les anomalies chromosomiques, les anomalies du chromosome 5 et du chromosome 20 sont récurrentes. L étude systématique, par hybridation in situ fluorescente (FISH) avec des sondes spécifiques de ces remaniements, a permis la caractérisation de leur structure puis l identification de leurs points de cassure afin de délimiter leurs régions délétées et conservées. Des régions communes délétées (RCD) et conservées (RCC) ont alors été déterminées. Ce travail a consisté à spécifier les anomalies des chromosomes 5 et 20 en délétions pures, dérivés de translocation, dérivés complexes, dicentriques, tricentriques, isochromosomes et isodérivés. Nous avons identifié des RCD et/ou des RCC pour chaque sous-groupe d anomalies chromosomiques. Pour l ensemble des réarrangements du chromosome 5, nous n avons pas déterminé de RCD, mais la région la plus souvent délétée est la région 5q31.1 à 5q31.2 qui comprend notamment les gènes EGRI, CTNNAI. Cette étude a démontré l existence d une RCC comprenant la région qui s étend de 5p10 à 5p13.1 et qui comprend des gènes probablement impliqués dans la survie et la prolifération cellulaires. La perte des gènes APC et NPM1 est variable dans les remaniements du chromosome 5. L haploinsuffisance de ces gènes peut expliquer les différents phénotypes des SM.D. Concernant l ensemble des anomalies du chromosome 20, nous n avons pas identifié de RCD, ni de RCC. Cependant la région la plus souvent délétée est la bande 20q12 et les régions les plus conservées sont les sous-bandes 20q11.21 et 20ql3.13, impliquant également des oncogènes ou gènes suppresseurs de tumeurs. Ce travail montre également l implication du gène ASXL1 qui peut être délété, conservé, amplifié ou rompu. L expression variable de ce gène pourrait expliquer les répercussions cliniques différentes des SMD avec anomalies du chromosome 20. Etant donné l hétérogénéité des remaniements des chromosomes 5 et 20, l analyse cytogénétique, incluant l étude des régions spécifiques dos chromosomes 5 et 20, par les techniques de FISH, est nécessaire afin de mieux comprendre les mécanismes oncogénétiques des SMD.Myelodysplastic syndromes are a heterogeneous biological and clinical entity in myeloid hemopathies. Clonal cytogenetic abnormalities are observed in 50% of the patients. Rearrangements of chromosomes 5 and 20 are recurrent in MDS. Precise characterization of rearrangements of chromosomes 5 and 20, delineation of deleted and retained regions were performed by fluorescent in situ hybridization (FISH) with specific probes. We determined commonly deleted regions (CDR) and commonly retained regions (CRR). This work allowed the specification of structural rearrangements in true deletions, derivatives from translocation, complex derivatives, dicentrics, tricentrics, isochromosomes and isoderivatives. We identified CDR and/or CRR in each group with chromosomal abnormalities. No CDR was observed in the whole group of chromosome 5 rearrangements, but the most frequently deleted region was Sq31.1 -5q31.2 band. A CRR was observed from 5p10 to 5p13.l. bands containing genes involved in cell survival and proliferation. The loss of APC and NPM1 genes was variable, suggesting that haploinsufficiency or not could explain different phonotypes in MDS. Concerning the whole group of chromosome 20 rearrangements, neither RCD nor RCC was identified. However, the most commonly deleted region was 20q12 and die most retained regions were 20q11.21 and 20q13.13 involving oncogenes and tumor suppressor genes. In this study, the ASXL1 gene was found deleted, retained, amplified or disrupted. Variable expression of ASXL1 may explain different clinical effects of MDS with chromosome 20 rearrangements. Cytogenetic analysis, including study of specific regions of chromosomes 5 and 20 by FISH, is necessary to understand the oncogenetic mechanisms involved in MDS.BREST-BU Médecine-Odontologie (290192102) / SudocSudocFranceF

Etude de la ségrégation méiotique par cytogénétique moléculaire chez des hommes infertiles présentant des troubles de la spermatogenèse

BREST-BU Médecine-Odontologie (290192102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

RBM22, a Key Player of Pre-mRNA Splicing and Gene Expression Regulation, Is Altered in Cancer

International audienceRNA-Binding Proteins (RBP) are very diverse and cover a large number of functions in the cells. This review focuses on RBM22, a gene encoding an RBP and belonging to the RNA-Binding Motif (RBM) family of genes. RBM22 presents a Zinc Finger like and a Zinc Finger domain, an RNA-Recognition Motif (RRM), and a Proline-Rich domain with a general structure suggesting a fusion of two yeast genes during evolution: Cwc2 and Ecm2. RBM22 is mainly involved in pre-mRNA splicing, playing the essential role of maintaining the conformation of the catalytic core of the spliceosome and acting as a bridge between the catalytic core and other essential protein components of the spliceosome. RBM22 is also involved in gene regulation, and is able to bind DNA, acting as a bona fide transcription factor on a large number of target genes. Undoubtedly due to its wide scope in the regulation of gene expression, RBM22 has been associated with several pathologies and, notably, with the aggressiveness of cancer cells and with the phenotype of a myelodysplastic syndrome. Mutations, enforced expression level, and haploinsufficiency of RBM22 gene are observed in those diseases. RBM22 could represent a potential therapeutic target in specific diseases, and, notably, in cancer

Cytogenetic and Genetic Abnormalities with Diagnostic Value in Myelodysplastic Syndromes (MDS): Focus on the Pre-Messenger RNA Splicing Process

Myelodysplastic syndromes (MDS) are considered to be diseases associated with splicing defects. A large number of genes involved in the pre-messenger RNA splicing process are mutated in MDS. Deletion of 5q and 7q are of diagnostic value, and those chromosome regions bear the numbers of splicing genes potentially deleted in del(5q) and del(7q)/-7 MDS. In this review, we present the splicing genes already known or suspected to be implicated in MDS pathogenesis. First, we focus on the splicing genes located on chromosome 5 (HNRNPA0, RBM27, RBM22, SLU7, DDX41), chromosome 7 (LUC7L2), and on the SF3B1 gene since both chromosome aberrations and the SF3B1 mutation are the only genetic abnormalities in splicing genes with clear diagnostic values. Then, we present and discuss other splicing genes that are showing a prognostic interest (SRSF2, U2AF1, ZRSR2, U2AF2, and PRPF8). Finally, we discuss the haploinsufficiency of splicing genes, especially from chromosomes 5 and 7, the important amplifier process of splicing defects, and the cumulative and synergistic effect of splicing genes defects in the MDS pathogenesis. At the time, when many authors suggest including the sequencing of some splicing genes to improve the diagnosis and the prognosis of MDS, a better understanding of these cooperative defects is needed