La translocation chromosomique t(X;6) (p11;q23) dans la leucémie aigüe à basophiles

Les leucémies aiguës myéloblastiques de l'enfant sont des hémopathies malignes associées majoritairement à des translocations chromosomiques. La caractérisation moléculaire de ces réarrangements chromosomiques permet de mettre en évidence des gènes importants dans les processus de différenciation hématopoïétique. D'un point de vue clinique, la découverte de translocations récurrentes peut aider à la recherche de maladie résiduelle, établir des valeurs pronostiques et ainsi adapter la prise en charge du patient. La leucémie aiguë à basophiles (LAB) est un sous-type rare de leucémie aiguë myéloblastique. Malgré de rares cas de translocation t(X;6)(p11;q23) décrits dans cette pathologie, jusqu'alors, aucune caractérisation moléculaire n'avait été effectuée. Nos travaux ont porté sur la caractérisation des remaniements géniques associés à cette translocation. Nous avons recherché les modifications issues de cet événement chez 4 nourrissons de sexe masculin porteurs de la t(X;6). De part sa localisation en 6q23, l'implication du gène MYB était suspectée. A l'aide des techniques de Fluorescence in situ Hybridization et de Rapid Amplification of cDNA ends, des réarrangements chromosomiques complexes ainsi que l'existence d'un gène chimérique, MYB-GATA1, ont été respectivement mis en évidence dans les cas de LAB étudiés. De plus, la translocation t(X;6) est associée à une invalidation de l'unique allèle sauvage du gène GATA1 situé sur le chromosome X. Ces deux gènes sont des acteurs majeurs de l'hématopoïèse. En effet, GATA1 est indispensable à une érythropoïèse normale et MYB est impliqué, entre autre, dans l'auto-renouvellement des cellules souches hématopoïétiques et dans la différenciation des progéniteurs myéloïdes. Des tests clonogéniques sur des progéniteurs hématopoïétiques murins exprimant la protéine chimérique MYB-GATA1 ont permis de caractériser son impact sur la différenciation myéloïde. MYB-GATA1 induit à la fois l'engagement de ces cellules dans la lignée granulocytaire, et leur blocage à un stade précoce de différenciation. De plus, cette protéine de fusion augmente le pouvoir clonogène des cellules transduites. Pour la première fois, l'ensemble de nos résultats établit un lien de cause à effet entre une translocation chromosomique récurrente et le développement de LAB.Childhood acute myeloblastic leukemias are haematological malignancies frequently associated with chromosomal translocations. The molecular characterization of these chromosomal rearrangements highlights genes important in haematopoietic differentiation. Furthermore, the discovery of recurrent chromosomal translocation is essential for the detection of residual disease, establishment of prognostic value and therapeutic choices. Acute basophilic leukemia is a rare sub-type of acute myeloblastic leukaemia. Despite rare cases of t(X;6)(p11;q23) translocation reported for this pathology, no molecular characterization was available until recently. The aim of our work was to characterize genes rearrangement in four cases of male infants carrying t(X;6). Because of its location on chromosome 6q23, MYB was a good candidate gene. Our molecular investigations, based on fluorescence in situ hybridization and rapid amplification of cDNA ends, revealed a complex chromosomal rearrangement leading to the creation of a MYB-GATA1 fusion gene. Moreover, this translocation is associated with an invalidation of the GATA1 gene located on chromosome X. These two proteins are master regulators of haematopoiesis. GATA1 is essential for normal erythropoiesis and MYB is involved in hematopoietic stem cell renewal and myeloid differentiation. Expression of MYB-GATA1 in mouse lineage-negative cells committed them to the granulocyte lineage and blocked them at an early stage of differentiation. Moreover, this protein increased clonogenic potential. Taken together, these results establish, for the first time, a link between a recurrent chromosomal translocation and the development of this particular subtype of infant leukemi

Key contribution of eIF4H-mediated translational control in tumor promotion.

Dysregulated expression of translation initiation factors has been associated with carcinogenesis, but underlying mechanisms remains to be fully understood. Here we show that eIF4H (eukaryotic translation initiation factor 4H), an activator of the RNA helicase eIF4A, is overexpressed in lung carcinomas and predictive of response to chemotherapy. In lung cancer cells, depletion of eIF4H enhances sensitization to chemotherapy, decreases cell migration and inhibits tumor growth in vivo, in association with reduced translation of mRNA encoding cell-proliferation (c-Myc, cyclin D1) angiogenic (FGF-2) and anti-apoptotic factors (CIAP-1, BCL-xL). Conversely, each isoform of eIF4H acts as an oncogene in NIH3T3 cells by stimulating transformation, invasion, tumor growth and resistance to drug-induced apoptosis together with increased translation of IRES-containing or structured 5'UTR mRNAs. These results demonstrate that eIF4H plays a crucial role in translational control and can promote cellular transformation by preferentially regulating the translation of potent growth and survival factor mRNAs, indicating that eIF4H is a promising new molecular target for cancer therapy

Myeloid cell differentiation arrest by miR-125b-1 in myelodysplasic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation

Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34+ cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity

La translocation chromosomique t(X;6) (p11;q23) dans la leucémie aigüe à basophiles

TOULOUSE3-BU Sciences (315552104) / SudocSudocFranceF

RNA editing in acute myeloid leukaemia with normal karyotype

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MiR-497 suppresses cycle progression through an axis involving CDK6 in ALK-positive cells.

International audienceAnaplastic large-cell lymphoma, a T cell neoplasm, is primarily a pediatric disease. 75% of pediatric anaplastic large-cell lymphoma cases harbor the chromosomal translocation t(2;5)(p23;q35) leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. NPM-ALK consists of an N-terminal nucleophosmin (NPM) domain fused to an anaplastic lymphoma kinase (ALK) cytoplasmic domain. Pediatric NPM-ALK(+) anaplastic large-cell lymphoma is often a disseminated disease and young patients are prone to chemoresistance or relapse shortly after chemotherapeutic treatment. Furthermore, there is no gold standard protocol for the treatment of relapses. To the best of our knowledge, this is the first study on the potential role of the microRNA, miR-497, in NPM-ALK(+) anaplastic large-cell lymphoma tumorigenesis. Our results show that miR-497 expression is repressed in NPM-ALK(+) cell lines and patient samples through the hypermethylation of its promoter and the activity of NPM-ALK is responsible for this epigenetic repression. We demonstrate that overexpression of miR-497 in human NPM-ALK(+) anaplastic large-cell lymphoma cells inhibits cellular growth and causes cell cycle arrest by targeting CDK6, E2F3 and CCNE1 - the three regulators of the G1 phase of the cell cycle. Interestingly, we show that a scoring system based on CDK6, E2F3 and CCNE1 expression could help identify relapsing pediatric patients. In addition, we demonstrate the sensitivity of NPM-ALK(+) cells to CDK4/6 inhibition using for the first time a selective inhibitor, Palbociclib. Together, our findings suggest that CDK6 could be a therapeutic target for the development of future treatments for NPM-ALK(+) anaplastic large-cell lymphoma

Doxorubicin-induced loss of DNA topoisomerase II and DNMT1- dependent suppression of MiR-125b induces chemoresistance in ALK-positive cells

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PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

International audiencePAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in BALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human BALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in BALL development, we generated a knockin mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed BALL with an incidence of 80%. Leukemic transformation was associated with recurrent secondary mutations on Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN-regulated gene candidates that establish the molecular bases of the pre-leukemic state to drive BALL initiation. Hence, our study provides a new in vivo model of human BALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development

Reversal of microRNA-150 silencing disadvantages crizotinib-resistant NPM-ALK(+) cell growth

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