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Rodriguez R, Rosu-Myles M, Aráuzo-Bravo M, Horrillo A, Pan Q, Gonzalez-Rey E, Delgado M, Menendez P

Human Bone Marrow Stromal Cells Lose Immunosuppressive and Anti-inflammatory Properties upon Oncogenic Transformation.

Stem Cell Reports 14 Oct 2014, 3 (4) 606-19. Epub 11 Sep 2014
Because of their immunomodulatory properties, human bone marrow stromal cells (hBMSCs) represent promising stem cells for treatment of immune disorders. hBMSCs expansion precedes their clinical use, so the possibility that hBMSCs undergo spontaneous transformation upon long-term culture should be addressed. Whether hBMSCs retain immunosuppressive and anti-inflammatory properties upon oncogenic transformation remains unknown. Using sequentially mutated hBMSCs and spontaneously transformed hBMSCs, we report that, upon oncogenic transformation, hBMSCs lose immunosuppressive and anti-inflammatory properties in vitro and in vivo. Transcriptome profiling and functional assays reveal immune effectors underlying the loss of immunomodulation in transformed hBMSCs. They display a proinflammatory transcriptomic signature, with deregulation of immune and inflammatory modulators and regulators of the prostaglandin synthesis. Transformed hBMSCs lose their capacity to secrete the immunosuppressive prostacyclins prostaglandin E2 (PGE2) and PGI2 but produce proinflammatory thromboxanes. Together, the immunoregulatory profile adopted by hBMSCs largely depends on intrinsic genetic-molecular determinants triggered by genomic instability/oncogenic transformation.
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Toscano MG, Navarro-Montero O, Ayllon V, Ramos-Mejia V, Guerrero-Carreno X, Bueno C, Romero T, Lamolda M, Cobo M, Martin F, Menendez P, Real PJ

SCL/TAL1-mediated transcriptional network enhances megakaryocytic specification of human embryonic stem cells.

Mol. Ther. 8 Oct 2014, . Epub 8 Oct 2014
Human embryonic stem cells (hESCs) are a unique in vitro model for studying human developmental biology and represent a potential source for cell replacement strategies. Platelets can be generated from cord blood progenitors and hESCs; however, the molecular mechanisms and determinants controlling the in vitro megakaryocytic specification of hESCs remain elusive. We have recently shown that SCL overexpression accelerates the emergence of hemato-endothelial progenitors from hESCs and promotes their subsequent differentiation into blood cells with higher clonogenic potential. Given that SCL participates in megakaryocytic commitment, we hypothesized that it may potentiate megakaryopoiesis from hESCs. We show that ectopic SCL expression enhances the emergence of megakaryocytic precursors, mature megakaryocytes and platelets in vitro. SCL-overexpressing megakaryocytes and platelets respond to different activating stimuli similarly to their control counterparts. Gene expression profiling of megakaryocytic precursors shows that SCL-overexpression renders a megakaryopoietic molecular signature. Connectivity Map analysis reveals that trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), both histone deacetylase (HDAC) inhibitors, functionally mimic SCL-induced effects. Finally, we confirm that both TSA and SAHA treatment promote the emergence of CD34+ progenitors, whereas valproic acid, another HDAC inhibitor, potentiates megakaryocyte and platelet production. We demonstrate that SCL and HDAC inhibitors are megakaryopoiesis regulators in hESCs.Molecular Therapy (2014); doi:10.1038/mt.2014.196.
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Diaz A, Puig-Butillé JA, Muñoz C, Costa D, Díez A, Garcia-Herrera A, Carrera C, Badenas C, Solé F, Malvehy J, Puig S, Alos L

TERT gene amplification is associated with poor outcome in acral lentiginous melanoma.

J. Am. Acad. Dermatol. Oct 2014, 71 (4) 839-41. More information
Fernández AF, Bayón GF, Urdinguio RG, Toraño EG, García MG, Carella A, Petrus-Reurer S, Ferrero C, Martinez-Camblor P, Cubillo I, García-Castro J, Delgado-Calle J, Pérez-Campo FM, Riancho JA, Bueno C, Menéndez P, Mentink A, Mareschi K, Claire F, Fagnani C, Medda E, Toccaceli V, Brescianini S, Moran S, Esteller M, Stolzing A, de Boer J, Nisticó L, Stazi MA, Fraga MF

H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells.

Genome Res. 30 Sep 2014, . Epub 30 Sep 2014
In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone posttranslational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells obtained from individuals aged 2 to 92 identified 18735 hypermethylated and 45407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on non-genetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type and chromatin context involved, and that, depending on the locus, the changes can be modulated by genetic and/or external factors.
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Schneider RK, Ademà V, Heckl D, Järås M, Mallo M, Lord AM, Chu LP, McConkey ME, Kramann R, Mullally A, Bejar R, Solé F, Ebert BL

Role of Casein Kinase 1A1 in the Biology and Targeted Therapy of del(5q) MDS.

Cancer Cell 17 Sep 2014, . Epub 17 Sep 2014
The casein kinase 1A1 gene (CSNK1A1) is a putative tumor suppressor gene located in the common deleted region for del(5q) myelodysplastic syndrome (MDS). We generated a murine model with conditional inactivation of Csnk1a1 and found that Csnk1a1 haploinsufficiency induces hematopoietic stem cell expansion and a competitive repopulation advantage, whereas homozygous deletion induces hematopoietic stem cell failure. Based on this finding, we found that heterozygous inactivation of Csnk1a1 sensitizes cells to a CSNK1 inhibitor relative to cells with two intact alleles. In addition, we identified recurrent somatic mutations in CSNK1A1 on the nondeleted allele of patients with del(5q) MDS. These studies demonstrate that CSNK1A1 plays a central role in the biology of del(5q) MDS and is a promising therapeutic target.
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