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Dalgaard K, Landgraf K, Heyne S, Lempradl A, Longinotto J, Gossens K, Ruf M, Orthofer M, Strogantsev R, Selvaraj M, Lu TT, Casas E, Teperino R, Surani MA, Zvetkova I, Rimmington D, Tung YC, Lam B, Larder R, Yeo GS, O'Rahilly S, Vavouri T, Whitelaw E, Penninger JM, Jenuwein T, Cheung CL, Ferguson-Smith AC, Coll AP, Körner A, Pospisilik JA

Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.

Cell 28 Jan 2016, 164 (3) 353-64.
More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28(+/D9) mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine. VIDEO ABSTRACT.
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Borghesan M, Fusilli C, Rappa F, Panebianco C, Rizzo G, Oben JA, Mazzoccoli G, Faulkes C, Pata I, Agodi A, Rezaee F, Minogue S, Warren A, Peterson A, Sedivy JM, Douet J, Buschbeck M, Cappello F, Mazza T, Pazienza V, Vinciguerra M

DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression.

Cancer Res. 15 Jan 2016, . Epub 15 Jan 2016
Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression. Cancer Res; 76(3); 1-13. ©2016 AACR.
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Palomo M, Mir E, Rovira M, Escolar G, Carreras E, Diaz-Ricart M

What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance.

Blood 11 Jan 2016, . Epub 11 Jan 2016
Defibrotide (DF) has received EMA authorization to treat sinusoidal obstruction syndrome, an early complication after hematopoietic cell transplantation. DF has a recognized role as an endothelial protective agent, although its precise mechanism of action remains to be elucidated. The aim of the present study was to investigate the interaction of DF with endothelial cells (ECs). A human hepatic endothelial cell line was exposed to different DF concentrations, previously labelled. Using inhibitory assays and flow cytometry techniques along with confocal microscopy, we explored: DF-EC interaction, endocytic pathways, and internalization kinetics. Moreover, we evaluated the potential role of adenosine receptors in DF-EC interaction and if DF effects on endothelium were dependent of its internalization. Confocal microscopy showed interaction of DF with EC membranes followed by internalization, though DF did not reach cell nucleus even after 24h. Flow cytometry revealed concentration, temperature and time dependent up-take of DF in two EC models but not in other cell types. Moreover, inhibitory assays indicated that entrance of DF into ECs occurs primarily through macropinocytosis. Our experimental approach did not show any evidence of the involvement of adenosine receptors in DF-EC interaction. The anti-inflammatory and antioxidant properties of DF seem to be due to the interaction of the drug with the cell membrane. Our findings contribute to a better understanding of the precise mechanisms of action of DF as a therapeutic and potential preventive agent on the endothelial damage underlying different pathological situations.
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Costa D, Muñoz C, Carrió A, Arias A, Gómez C, Solé F, Espinet B, Azaceta G, Calasanz MJ, Nomdedeu M, Calvo X, Campo E, Nomdedeu B

Refining the Breakpoints of Three New Translocations Identified in Myelodysplastic Syndromes.

Acta Haematol. 2016, 135 (2) 94-100. Epub 28 Oct 2015
Recurrent translocations are uncommon in myelodysplastic syndromes (MDS). Three new recurrent translocations, namely der(12)t(3;12)(q13;p13), t(11;13;22)(q13;q14;q12) and der(17)t(13;17)(q21;p13), identified by conventional cytogenetics (CC) in 4 MDS patients, were further characterized using a panel of commercial and homemade fluorescence in situ hybridization (FISH) probes. The goal of this study was to determine the precise breakpoints and to identify genes that could be related with the neoplastic process. Half of the breakpoints (4/8) were precisely identified and in the remaining half they were narrowed to a region ranging from 14 to 926 kb. All the studied breakpoints had interstitial or terminal deletions ranging from 536 kb to 89 Mb, and only those 7 Mb were detected by CC. The genes located in or around the breakpoints described in our study have not been previously related to MDS. The deleted regions include the ETV6 and RB1 genes, among others, and exclude the TP53 gene. FISH studies were useful to refine the breakpoints of the translocations, but further studies are needed to determine the role of the involved genes in the neoplastic process.
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Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.

Lancet Oncol. 3 Dec 2015, . Epub 3 Dec 2015
Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
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