64 research outputs found
Disappearance of slan-positive non-classical monocytes for diagnosis of chronic myelomonocytic leukemia with an associated inflammatory state
International audienceNo abstract availabl
The zCOSMOS 10k-Bright Spectroscopic Sample
We present spectroscopic redshifts of a large sample of galaxies with I_(AB) < 22.5 in the COSMOS field, measured from spectra of 10,644 objects that have been obtained in the first two years of observations in the zCOSMOS-bright redshift survey. These include a statistically complete subset of 10,109 objects. The average accuracy of individual redshifts is 110 km s^(â1), independent of redshift. The reliability of individual redshifts is described by a Confidence Class that has been empirically calibrated through repeat spectroscopic observations of over 600 galaxies. There is very good agreement between spectroscopic and photometric redshifts for the most secure Confidence Classes. For the less secure Confidence Classes, there is a good correspondence between the fraction of objects with a consistent photometric redshift and the spectroscopic repeatability, suggesting that the photometric redshifts can be used to indicate which of the less secure spectroscopic redshifts are likely right and which are probably wrong, and to give an indication of the nature of objects for which we failed to determine a redshift. Using this approach, we can construct a spectroscopic sample that is 99% reliable and which is 88% complete in the sample as a whole, and 95% complete in the redshift range 0.5 < z < 0.8. The luminosity and mass completeness levels of the zCOSMOS-bright sample of galaxies is also discussed
Mass and environment as drivers of galaxy evolution in SDSS and zCOSMOS and the origin of the Schechter function
We explore the inter-relationships between mass, star-formation rate and
environment in the SDSS, zCOSMOS and other surveys. The differential effects of
mass and environment are completely separable to z ~ 1, indicating that two
distinct processes are operating, "mass-quenching" and "environment-quenching".
Environment-quenching, at fixed over-density, evidently does not change with
epoch to z ~ 1, suggesting that it occurs as large-scale structure develops in
the Universe. The observed constancy of the mass-function shape for
star-forming galaxies, demands that the mass-quenching of galaxies around and
above M*, must be proportional to their star-formation rates at all z < 2. We
postulate that this simple mass-quenching law also holds over a much broader
range of stellar mass and epoch. These two simple quenching processes, plus
some additional quenching due to merging, then naturally produce (a) a
quasi-static Schechter mass function for star-forming galaxies with a value of
M* that is set by the proportionality between the star-formation and
mass-quenching rates, (b) a double Schechter function for passive galaxies with
two components: the dominant one is produced by mass-quenching and has exactly
the same M* as the star-forming galaxies but an alpha shallower by +1, while
the other is produced by environment effects and has the same M* and alpha as
the star-forming galaxies, and is larger in high density environments.
Subsequent merging of quenched galaxies modifies these predictions somewhat in
the denser environments, slightly increasing M* and making alpha more negative.
All of these detailed quantitative relationships between the Schechter
parameters are indeed seen in the SDSS, lending strong support to our simple
empirically-based model. The model naturally produces for passive galaxies the
"anti-hierarchical" run of mean ages and alpha-element abundances with mass.Comment: 66 pages, 19 figures, 1 movie, accepted for publication in ApJ. The
movie is also available at
http://www.exp-astro.phys.ethz.ch/zCOSMOS/MF_simulation_d1_d4.mo
Role of ASXL2 in Normal and Malignant Hematopoiesis
Les gĂšnes ASXL (ASXL1, ASXL2 et ASXL3) sont les homologues mammifĂšres du gĂšne Additional sex combs (Asx) prĂ©sent chez la Drosophile. En 2009, des mutations somatiques impliquant ASXL1 ont Ă©tĂ© identifiĂ©es chez ~ 10-20% des patients atteints dâhĂ©mopathies myĂ©loĂŻdes. Le rĂŽle et lâimplication des autres membres de la famille dans lâhĂ©matopoĂŻĂšse normale et pathologique sont encore inconnus.Dans ce travail, nous avons identifiĂ© pour la 1Ăšre fois, par sĂ©quençage haut dĂ©bit, des mutations somatiques rĂ©currentes dâASXL2 (22,7%) chez des adultes et enfants atteints de leucĂ©mies aiguĂ«s myĂ©loĂŻdes (LAM) avec translocation t(8 ;21) (c.-Ă -d AML1-ETO (AE) ou RUNX1/RUNX1T1). Ces mutations nâont pas Ă©tĂ© retrouvĂ©es dans dâautres sous types de LAM et sont mutuellement exclusives des mutations dâASXL1. Le sĂ©quençage de l'ARN (RNAseq) d'Ă©chantillons de patients a rĂ©vĂ©lĂ© un profil transcriptionnel spĂ©cifique chez les patients mutĂ©s pour ASXL2. Bien que la survie globale soit similaire, les patients porteurs de mutations dâASXL1 ou ASXL2 ont une incidence cumulative de rechute de 54,6% et 36,0% comparativement Ă 25% pour les patients non mutĂ©s (P = 0,226). Ces rĂ©sultats, Ă©voquant une coopĂ©ration entre ASXL1/2 et AE lors de la leucĂ©mogenĂšse, sont importants car les t(8 ;21) sont parmi les anomalies cytogĂ©nĂ©tiques les plus frĂ©quentes en matiĂšre de LAM. Dâautre part, il est bien Ă©tabli que AE nĂ©cessite la coopĂ©ration dâaltĂ©rations gĂ©niques supplĂ©mentaires pour induire la leucĂ©mie.Nous avons ensuite explorĂ© le rĂŽle dâASXL2 dans lâhĂ©matopoĂŻĂšse normale. Nous avons dâabord dĂ©montrĂ© in vitro que les mutations dâASXL2 entrainent une diminution de son expression. Nous avons ensuite gĂ©nĂ©rĂ© un modĂšle de souris invalidĂ©es pour Asxl2 (KO conditionnel). Par transplantations compĂ©titive et non compĂ©titive, nous avons montrĂ© que le KO pour Asxl2 ou Asxl1 et Asxl2 (double KO) induit une diminution et un dĂ©faut dâauto renouvellement des cellules souches hĂ©matopoĂŻĂ©tiques (CSH) ainsi que des cytopĂ©nies, avec un phĂ©notype plus sĂ©vĂšre que le KO dâAsxl1 seul. Lâanalyse du transcriptome (par RNAseq) des CSH a rĂ©vĂ©lĂ© un nombre de gĂšnes dĂ©rĂ©gulĂ©s par la perte dâAsxl2 25 fois plus important quâavec Asxl1. De plus les gĂšnes dĂ©rĂ©gulĂ©s par la perte dâAsxl2 recoupent les cibles transcriptionnelles dâAML1-ETO. Ces donnĂ©es suggĂ©rant quâAsxl2 pourrait ĂȘtre un mĂ©diateur important de la leucĂ©mogenĂšse, nous avons ensuite Ă©tudiĂ© le rĂŽle dâASXL2 dans les LAM avec t(8 ;21). In vitro, par CHIP Seq, nous avons mis en Ă©vidence, dans des lignĂ©es t(8;21), un enrichissement des sites de liaisons Ă lâADN dâASXL2 au niveau de ceux dâAML1-ETO. De plus, en infectant ces lignĂ©es avec un shRNA dirigĂ© contre ASXL2, nous avons Ă©tudiĂ© la marque H3K4me1 qui est augmentĂ©e de façon majeure dans le contexte leucĂ©mique. Afin de comprendre les effets in vivo dâASXL2 dans la leucĂ©mogenĂšse, nous avons rĂ©alisĂ© des greffes de cellules de moelle osseuse de souris KO infectĂ©es avec un rĂ©trovirus pour AE9a. Ces souris dĂ©veloppent une LAM plus rapidement que les souris contrĂŽles AE9a lors de greffes secondaires, suggĂ©rant Ă nouveau un rĂŽle spĂ©cifique dâAsxl2. Afin dâĂ©lucider le mĂ©canisme impliquĂ©, nous avons rĂ©alisĂ© de lâATAC seq sur ces souris et mis en Ă©vidence des diffĂ©rences importantes dans lâaccessibilitĂ© de la chromatine, notamment au niveau des gĂšnes Hoxa et Meis1.Pour la premiĂšre fois, nous dĂ©crivons lâincidence des mutations dâASXL2 dans les LAM et le rĂŽle dâASXL2 dans lâhĂ©matopoĂŻĂšse. Nous suggĂšrerons un rĂŽle spĂ©cifique dans les LAM avec t(8;21), qui pourrait ĂȘtre associĂ© Ă des modifications de la marque dâhistone H3K4me1. Ces spĂ©cificitĂ©s pourraient rĂ©sulter en de nouvelles options thĂ©rapeutiques chez les patients.The ASXL family of genes (ASXL1, ASXL2, and ASXL3) are mammalian homologs of the Drosophilia Additional sex combs (Asx) gene. In 2009 somatic mutations involving ASXL1 were originally identified in ~10-20% of patients with myeloid malignancies. Despite this association, alterations in other ASXL family members and their potential function in normal or malignant hematopoiesis were unknown.We identified, by next generation sequencing, the surprising finding of highly recurrent somatic ASXL2 mutations (22.7%) in adult and pediatric acute myeloid leukemia (AML) patients bearing the AML1-ETO (AE) translocation (i.e. RUNX1/RUNX1T1, t(8;21)). Interestingly these mutations were only found in patients with t(8 ;21) and mutually exclusive with ASXL1 mutations. RNA sequencing (RNAseq) of primary AE AML patient samples revealed that ASXL2-mutants form a distinct transcriptional subset of AE AML. Although overall survival was similar between ASXL1 and ASXL2 mutant t(8;21) AML patients and their wild-type counterparts, patients with ASXL1 or ASXL2 mutations had a cumulative incidence of relapse of 54.6% and 36.0%, respectively, compared with 25% in ASXL1/2 wild-type counterparts (P=0.226). These findings are of immediate biological importance as AE translocations are amongst the most common cytogenetic alterations in AML and it is well established that AE requires additional genetic alterations to induce leukemogenesis.Given the above human genetic data, we set out to perform a functional comparison of ASXL1 and ASXL2 on hematopoiesis and determine the functional basis for frequent mutations in AE AML. In vitro analyses of ASXL2 mutations revealed that these mutations resulted in substantial reduction of ASXL2 protein expression. We therefore generated Asxl2 conditional knockout (cKO) mice to delineate the effect of ASXL2 loss on hematopoiesis. Competitive and noncompetitive transplantation revealed that Asxl2 or compound Asxl1/2 loss resulted in cell-autonomous, rapid defects of hematopoietic stem cell (HSC) function, self-renewal, and number with peripheral blood leukopenia and thrombocytopenia. RNA-seq of HSCs revealed twenty-fold greater differentially expressed genes in Asxl2 cKO mice relative to Asxl1 cKO mice. Interestingly, genes differentially expressed with Asxl2 loss significantly overlapped with direct transcriptional targets of AE, findings not seen in Asxl1 cKO mice.Overall, the above data suggest that Asxl2 may be a critical mediator of AE leukemogenesis. To functionally interrogate the role of ASXL2 loss in leukemogenesis we first utilized an in vitro model with RNAi-mediated depletion of ASXL2 in the SKNO1 cell line. Anti-ASXL2 and AE ChIPSeq revealed significant co-occupancy of ASXL2 with AE binding sites. Moreover, analysis of histone modification ChIP-Seq revealed an enrichment in intergenic and enhancer H3K4me1 abundance following ASXL2 loss. Next, to understand the in vivo effects of Asxl2 loss in the context of AE, we performed retroviral bone marrow (BM) transplantation assays using AE9a in Asxl2 cKO mice. In contrast to the failure of HSC function with Asxl2 deletion alone, mice reconstituted with BM cells expressing AE9a in Asxl2-deficient background had a shortened leukemia-free survival compared to Asxl2-wildtype control. Moreover, ATAC Sequencing showed an increase of chromatin occupancy with Asxl2 loss at known leukemogenic loci, including the HoxA and Meis1 loci.Overall, these data reveal that ASXL2 is required for hematopoiesis and has differing biological and transcriptional functions from ASXL1. Moreover, this work identifies ASXL2 as a novel mediator of AE transcriptional function and provides a new model of penetrant AE AML based on genetic events found in a substantial proportion of t(8;21) AML patients. Further interrogation of the enhancer alterations generated by ASXL2 loss in AE AML may highlight new therapeutic approaches for this subset of AM
Impact de l'Imatinib sur la prévalence de la leucémie myéloïde chronique dans la région Nord-Pas-de-Calais
LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF
INRAtion 2.6, Programa informatico de calculo, analisis y gestion de raciones en rumiantes
International audienc
INRAtion 2.6, Programa informatico de calculo, analisis y gestion de raciones en rumiantes
International audienc
Recommended from our members
Distinct DNA Methylation and Expression Profiles Underlie CMML Responsiveness to Decitabine and Uncover Novel Mechanism of Resistance
Abstract Myelodysplastic syndromes (MDS) and the related disorder chronic myelomonocytic leukemia (CMML) are characterized by abnormal DNA hypermethylation and the DNA methyltransferase inhibitors (DMTis) azacytidine and decitabine (DAC) are frequently used as frontline therapy in these patients. However, DMTis are ineffective for ~50% of the patients who must still undergo treatment for at least 6 months before they can be deemed resistant. Therefore, it is of critical importance to identify baseline molecular differences associated with DMTi sensitivity that can help (i) to improve patient risk-stratification at diagnosis and (ii) identify the underlying mechanisms of resistance to these agents. Previous efforts to identify baseline DNA methylation differences at promoter regions between DMTi responders and non-responders have not been successful, so we hypothesized that any potential differences would be located distally from promoter regions. For this purpose we studied 40 CMML patients at diagnosis, all of whom had been uniformly treated with DAC 20 mg/m2/day x 5 days as frontline therapy. After 6 cycles of therapy patients were classified as responders (n=19, hematological improvement or better), or non-responders (n=21, stable or progressive disease). Mutational analysis showed no significant differences in the frequency of mutations in TET2, ASXL1, DNMT3A, RUNX1, TP53, JAK2, KIT, KRAS, EZH2, IDH1/2 and spliceosome genes. Using Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) we analyzed the baseline methylation status at ~3M CpG sites across the genome of 39/40 CMML patients. We identified 158 statistically significant differentially methylated regions (DMRs) (FDR<0.1 and methylation difference â„25%) between the two groups. DAC-sensitive patients displayed both regions of higher methylation as well as regions with lower methylation compared to DAC-resistant patients. As predicted, DMRs were depleted at promoters (DMRs 9% vs. Background [BG] 21%, p-value: 3.4Ă10-5) and CpG islands (DMRs 8% vs. BG 25%, p-value: 1.5Ă10-8). Further analysis showed that hypermethylated DMRs were enriched at intronic regions (Hyper DMRs 58% vs. BG 33%, p-value: 3.7Ă10-6) while hypomethylated DMRs were enriched at intergenic regions (Hypo DMRs 49% vs. BG 38%, p-value: 2.6Ă10-2). Moreover, hypermethylated DMRs were significantly enriched for enhancer regions, and in particular, enhancers located within gene bodies (hyper DMRs 38% vs. BG 18%, p-value: 2.3Ă10-5). KEGG pathway analysis showed a significant enrichment of DMRs in the MAPK signaling pathway (FDR<0.01). Next, using a support vector machine algorithm with 10-fold cross validation we were able to develop a classifier capable of predicting response to DAC with high level of accuracy (ROC AUC: 0.99) based solely on the DNA methylation status at diagnosis of 17 genomic regions. Three different random splits of the cohort into training and test sets achieved correct predictions for 85.7%, 89.47%, and 100% of cases, respectively, demonstrating the accuracy and potential utility of such a classifier. Finally, RNA-seq analysis identified 53 differentially expressed genes between responders (n=8) and non-responders (n=6) at diagnosis. Genes implicated in cell cycle and DNA replication were overexpressed in responders. By contrast, very few genes were overexpressed at the time of diagnosis in primary resistant patients. Among these were CXCL4 and CXCL7 which, given their reported contributions to cell cycle arrest and chemoresistance, were tested for their functional roles in DAC resistance. Pre-treatment of normal CD34+ cells for 72 h with 10nM DAC significantly reduced colony formation (p<0.05) but the addition of 50ng/mL of CXCL4 and CXCL7 restored colony formation to that of untreated cells. Moreover, treatment of primary CMML cells with 10 nM DAC for 72h significantly reduced viability of these cells, while concomitant treatment with 50ng/mL of CXCL4 and CXCL7 was sufficient to abrogate this effect. Taken together, our findings demonstrate that (i) specific DNA methylation profiles targeting non-promoter regulatory regions are associated with DAC sensitivity, (ii) these differences can be harnessed for the development of clinical biomarkers predictive of response and (iii) we identified a novel mechanism of resistance to DAC mediated through two chemokines that are exclusively overexpressed in non-responders. Disclosures No relevant conflicts of interest to declare
- âŠ