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Recent research has identified critical roles for microRNAs in a large number of cellular processes, including tumorigenic transformation. While significant progress has been made towards understanding the mechanisms of gene regulation by microRNAs, much less is known about factors affecting the expression of these noncoding transcripts. Here, we demonstrate for the first time a functional link between hypoxia, a well-documented tumor microenvironment factor, and microRNA expression. Microarray-based expression profiles revealed that a specific spectrum of microRNAs (including miR-23, -24, -26, -27, -103, -107, -181, -210, and -213) is induced in response to low oxygen, at least some via a hypoxia-inducible-factor-dependent mechanism. Select members of this group (miR-26, -107, and -210) decrease proapoptotic signaling in a hypoxic environment, suggesting an impact of these transcripts on tumor formation. Interestingly, the vast majority of hypoxia-induced microRNAs are also overexpressed in a variety of human tumors.

Las organizaciones actuales enfrentan condiciones cada vez más cambiantes que les exigen capacidad de adaptarse y mantenerse en el tiempo. El presente artículo propone un modelo conceptual e instrumental de sostenibilidad, que se fundamenta en diferentes concepciones y enfoques, con los cuales se ha abordado la realidad del ser humano en las organizaciones, a partir de la introducción del concepto de tejido social empresarial. La investigación de campo se realizó en un grupo de empresas del sector biotecnológico colombiano. Se planteó una nueva perspectiva en la administración del factor humano enfocada en la sostenibilidad organizacional, y centrada en el análisis de la realidad que experimentan las personas en las organizaciones de hoy.

MicroRNAs (miRNAs) are short noncoding RNAs regulating gene expression that play roles in human diseases, including cancer. Each miRNA is predicted to regulate hundreds of transcripts, but only few have experimental validation. In chronic lymphocytic leukemia (CLL), the most common adult human leukemia, miR-15a and miR-16-1 are lost or down-regulated in the majority of cases. After our previous work indicating a tumor suppressor function of miR-15a/16-1 by targeting the BCL2 oncogene, here, we produced a high-throughput profiling of genes modulated by miR-15a/16-1 in a leukemic cell line model (MEG-01) and in primary CLL samples. By combining experimental and bioinformatics data, we identified a miR-15a/16-1 -gene signature in leukemic cells. Among the components of the miR-15a/16-1 signature, we observed a statistically significant enrichment in AU-rich elements (AREs). By examining the Gene Ontology (GO) database, a significant enrichment in cancer genes (such as MCL1 , BCL2 , ETS1 , or JUN ) that directly or indirectly affect apoptosis and cell cycle was found.

Abstract 78 The treatment improvements in the past two decades led childhood acute lymphoblastic leukemia (ALL) cure rates reach over 80%, but children who carry the Philadelphia (Ph+) chromosome still have high risk of relapse due to therapy resistance. Different results with large series of patients have shown that an earlier remission after induction with glucocorticoids and intrathecal methotrexate is correlated to a better outcome. Besides, the minimal residual disease (MRD) risk measured after induction is also correlated to the therapy response, indicating that an early response can predict Ph+ ALL overall outcome. Several studies have shown that Ph+ ALL is heterogeneous in terms of clinical parameters even if all patients carry BCR-ABL and most of them carry the oncogenic isoform of IKAROS. They respond differently to the treatment, which suggests the presence of additional mechanisms involved in leukemogenesis. In an attempt to find secondary genetic abnormalities that may be responsible for the Ph+ ALL chemo resistance and heterogeneity, we studied the miRNA expression profile in two patient groups discriminated by the initial therapy response. We included samples from 78 consecutive Ph+ ALL children diagnosed in Italy between 2000 and 2010. The miRNA signature was analyzed by miRNA array using Applied Biosystems Array-Cards comparing two patient groups differentiated according to MRD and prednisone response. A particular miRNA profile was found in the poor responder group and it was confirmed using specific miRNA single assays from AB. Specially the miR-125b was up to ten-fold overexpressed compared to the good responder group (p =.006). To investigate the functional role of miR-125b in Ph+ ALL we used BCR-ABL positive cell lines (3 ALL and one CML in blast-crisis) to create a xenograft leukemia model and induced miRNA upregulation by direct inoculation of synthetic miR-125b (premiR). Tumors injected with premiR-125b (n=14) were significantly bigger than the scrambled oligonucleotide (n=10) and mock controls (n=4) (p=.04). After two weeks the premiR-125b tumors grew six-fold more than controls and average tumor weights for the scrambled oligonucleotides and the premiR-125b inoculated mice were 0.63 g and 1.56 g, respectively (p =.01). Further, we determined whether miR-125b protects the tumor cells from apoptosis after treatment with Dexamethasone. While tumors injected with scrambled molecules were 70% reduced after 10 days of corticoid treatment, tumors injected with premiR-125b were only 30% reduced (p=.05). Together, these results suggest that miR-125b acts as an oncogene in Ph+ ALL and its overexpression accelerates the role of BCR-ABL, increasing therapy resistance and leukemia aggressiveness. Additional studies will be necessary to understand why this miRNA is overexpressed in some patients and how it acts in cooperation with BCR-ABL to induce leukemia. In the future, novel therapies using miRNAs as targets can emerge as strategies to be added to the anti-tyrosine kinase drugs in order to improve treatment response and survivor in Ph+ ALL. Disclosures: No relevant conflicts of interest to declare.

BACKGROUND: MicroRNA expression profiles can be used to distinguish normal B cells from malignant B cells in patients with chronic lymphocytic leukemia (CLL). We investigated whether microRNA profiles are associated with known prognostic factors in CLL. METHODS: We evaluated the microRNA expression profiles of 94 samples of CLL cells for which the level of expression of 70-kD zeta-associated protein (ZAP-70), the mutational status of the rearranged immunoglobulin heavy-chain variable-region (IgV(H) ) gene, and the time from diagnosis to initial treatment were known. We also investigated the genomic sequence of 42 microRNA genes to identify abnormalities. RESULTS: A unique microRNA expression signature composed of 13 genes (of 190 analyzed) differentiated cases of CLL with low levels of ZAP-70 expression from those with high levels and cases with unmutated IgV(H) from those with mutated IgV(H) . The same microRNA signature was also associated with the presence or absence of disease progression. We also identified a germ-line mutation in the miR-16-1-miR-15a primary precursor, which caused low levels of microRNA expression in vitro and in vivo and was associated with deletion of the normal allele. Germ-line or somatic mutations were found in 5 of 42 sequenced microRNAs in 11 of 75 patients with CLL, but no such mutations were found in 160 subjects without cancer (P