Research publications

Found 1313 publicacions matching the indicated search criteria.
Miguel-Escalada I, Bonàs.Guarch S, Cebola I, Mendieta-Esteban,, Rolando DMY, Javierre B, Goutham A, Irene I, Morgan CC, García-Hurtado J, Beucher A, Morán I, Pasquali L, Ramos M, Appel EVR, Linneberg A, Gjesing PD, Witte R, Pederson O, Grarup N, Ravassard P, Torrents D, Kerr-Conte J, Pattou F, Fedko IO, Prokopenko I, Hansen T, Martí-Renom, Fraser P, Ferrer J

Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes

Nature Genetics (in press at 7 May 2019, .
Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer regions (enhancer clusters, stretch enhancers or super-enhancers). So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in 3D-space. Furthermore, their target genes are generally unknown. We have now created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers with their target genes, often located hundreds of kilobases away. It further revealed sets of islet enhancers, super-enhancers and active promoters that form 3D higher-order hubs, some of which show coordinated glucose-dependent activity. Hub genetic variants impact the heritability of insulin secretion, and help identify individuals in whom genetic variation of islet function is important for T2D. Human islet 3D chromatin architecture thus provides a framework for interpretation of T2D GWAS signals.
Watt S, Vasquez L, Walter K, Mann AL, Kundu K, Chen Lu, Yan Y, Ecker S, Burden F, Farrow S, Farr B, Iotchkova V, Elding H, Mead D, Tardaguila M, Ponstingl H, Fraser P, Richardson D, Datta A, Flicek P, Clarke L, Downes K, Pastinen T, Fraser P, Frontini M, Javierre BM, Spivakov M, Soranzo N

Variation in PU.1 binding and chromatin looping at neutrophil enhancers influences autoimmune disease susceptibility

bioRxiv 29 Apr 2019, . Epub 29 Apr 2019
Neutrophils play fundamental roles in innate inflammatory response, shape adaptive immunity1, and have been identified as a potentially causal cell type underpinning genetic associations with immune system traits and diseases2,3 The majority of these variants are non-coding and the underlying mechanisms are not fully understood. Here, we profiled the binding of one of the principal myeloid transcriptional regulators, PU.1, in primary neutrophils across nearly a hundred volunteers, and elucidate the coordinated genetic effects of PU.1 binding variation, local chromatin state, promoter-enhancer interactions and gene expression. We show that PU.1 binding and the associated chain of molecular changes underlie genetically-driven differences in cell count and autoimmune disease susceptibility. Our results advance interpretation for genetic loci associated with neutrophil biology and immune disease.
Ganster C, Müller-Thomas C, Haferlach C, Strupp C, Ogata K, Germing U, Hildebrandt B, Mallo M, Lübbert M, Müller C, Solé F, Götze KS, Vandenberghe P, Göhring G, Steinmetz T, Kröger N, Platzbecker U, Söling U, Raynaud S, Shirneshan K, Schanz J, Haase D

Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes.

Genes Chromosomes Cancer 17 Apr 2019, . Epub 17 Apr 2019
The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the new comprehensive cytogenetic scoring system for MDS, chromosome 7 anomalies are no longer generally assigned to poor risk features but are thoroughly separated. However, der(1;7)(q10;p10), hereinafter der(1;7), is merged into the group labeled "any other single" and belongs to the intermediate risk group, just by definition due to lack of adequate clinical data. The aim of our international collaborative was to clarify the "real" prognostic impact of der(1;7) on a homogenous and well-documented data base. We performed detailed analysis of 63 MDS patients with isolated der(1;7) constituting the largest cohort hitherto reported. Furthermore, clinical data are compared with those of patients with isolated del(7q) and isolated monosomy 7. Median overall survival (OS) of patients with der(1;7) is 26 months (hazard ratio (HR) 0.91 for del(7q) vs der(1;7) and 2.53 for monosomy 7 vs der(1;7)). The der(1;7) is associated with profound thrombocytopenia most probably causing the reduced OS which is in striking contrast to the low risk for AML transformation (HR 3.89 for del(7q) vs der(1;7) and 5.88 for monosomy 7 vs der(1;7)). Molecular karyotyping indicates that der(1;7) is generated in a single step during mitosis and that a chromosomal imbalance rather than a single disrupted gene accounts for malignancy. Thus, the current cytogenetic scoring system assigning isolated der(1;7) to the intermediate risk group is now confirmed by a sufficient data set.
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Rico LG, Juncà J, Ward MD, Bradford J, Petriz J

Correction: Is alkaline phosphatase the smoking gun for highly refractory primitive leukemic cells?

Oncotarget 19 Mar 2019, 10 (23) 2335. Epub 19 Mar 2019
[This corrects the article DOI: 10.18632/oncotarget.12497.].
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Valiollahi E, Ribera JM, Genescà E, Behravan J

Genome-wide identification of microRNA signatures associated with stem/progenitor cells in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Mol. Biol. Rep. Feb 2019, 46 (1) 1295-1306. Epub 2 Feb 2019
Acute lymphoblastic leukemia (ALL) is a malignant transformation with uncontrolled proliferation of lymphoid precursor cells within bone marrow including a dismal prognosis after relapse. Survival of a population of quiescent leukemia stem cells (LSCs, also termed leukemia-initiating cells (LICs)) after treatment is one of the relapse reasons in Ph
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Barba P, Morgades M, Montesinos P, Gil C, Fox ML, Ciudad J, Moreno MJ, González-Campos J, Genescà E, Martínez-Carballeira D, Martino R, Vives S, Guardia R, Mercadal S, Artola MT, Cladera A, Tormo M, Esteve J, Bergua J, Vall-Llovera F, Ribera J, Martínez-Sanchez P, Amigo ML, Bermúdez A, Calbacho M, Hernández-Rivas JM, Feliu E, Orfao A, Ribera JM

Increased survival due to lower toxicity for high-risk T-cell acute lymphoblastic leukemia patients in two consecutive pediatric-inspired PETHEMA trials.

Eur. J. Haematol. Jan 2019, 102 (1) 79-86. Epub 22 Nov 2018
Pediatric-inspired regimens have been adopted by several groups as the treatment strategy for adult patients with acute lymphoblastic leukemia (ALL). Whether subsequent modifications of these protocols have led to an improvement in the outcome of patients is uncertain, especially in T-cell ALL. We analyzed 169 patients with high-risk T-cell ALL included in two consecutive trials of the PETHEMA Group (HR-ALL03 [n = 104] and the more contemporary HR-ALL11 [n = 65]).
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Gachet S, El-Chaar T, Avran D, Genesca E, Catez F, Quentin S, Delord M, Thérizols G, Briot D, Meunier G, Hernandez L, Pla M, Smits WK, Buijs-Gladdines JG, Van Loocke W, Menschaert G, André-Schmutz I, Taghon T, Van Vlierberghe P, Meijerink JP, Baruchel A, Dombret H, Clappier E, Diaz JJ, Gazin C, de Thé H, Sigaux F, Soulier J

Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.

Cancer Discov Dec 2018, 8 (12) 1614-1631. Epub 28 Sep 2018
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14,
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Ribera JM, Ribera J, Genescà E

The role of stem cell transplantation in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia

Therapeutic Advances in Hematology Nov 2018, .
The concurrent administration of tyrosine kinase inhibitors (TKIs) with standard chemotherapy together with allogeneic hematopoietic stem cell transplantation (alloHSCT) has improved the outcome of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Although to date, no study has shown alloHSCT to be inferior to chemotherapy plus TKIs in any subgroup of adult Ph+ ALL, there is some evidence suggesting no additional benefit of alloHSCT in patients with deep molecular responses to intensive chemotherapy with a second-generation, and especially, third-generation TKI. As none of these positive and negative studies are controlled, randomized trials are needed to fully define the role of alloHSCT in Ph+ ALL, especially in those with deep molecular response. However, if studies combining TKIs with new approaches such as immunotherapy lead to durable responses, alloHSCT in the first complete remission could be avoided in the near future in the majority of patients with Ph+ ALL.
Rico LG, Juncà J, Ward MD, Bradford JA, Bardina J, Petriz J

Acoustophoretic Orientation of Red Blood Cells for Diagnosis of Red Cell Health and Pathology.

Sci Rep 24 Oct 2018, 8 (1) 15705. Epub 24 Oct 2018
Distortions of the normal bi-concave disc shape for red blood cells (RBCs) appear in a number of pathologies resulting from defects in cell membrane skeletal architecture, erythrocyte ageing, and mechanical damage. We present here the potential of acoustic cytometry for developing new approaches to light-scattering based evaluation of red blood cell disorders and of the effects of storage and ageing on changes or damage to RBCs membranes. These approaches could be used to immediately evaluate the quality of erythrocytes prior to blood donation and following transfusion. They could also be applied to studying RBC health in diseases and other pathologies, such as artificial heart valve hemolysis, thermal damage or osmotic fragility. Abnormal distributions of erythrocytes can typically be detected after just 30 to 45 seconds of acquisition time using 1-2 µL starting blood volumes.
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Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, Shima H, Aly M, Pastor V, Kuzmanovic T, Radivoyevitch T, Adema V, Awada H, Yoshida K, Li S, Sole F, Hanna R, Jha BK, LaFramboise T, Ogawa S, Sekeres MA, Wlodarski MW, Cammenga J, Maciejewski JP

Germline loss of function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes

Blood 15 Oct 2018, . Epub 15 Oct 2018More information