A novel molecular mechanism involved in multiple myeloma development revealed by targeting MafB to haematopoietic progenitors

Understanding the cellular origin of cancer can help to improve disease prevention and therapeutics. Human plasma cell neoplasias are thought to develop from either differentiated B cells or plasma cells. However, when the expression of Maf oncogenes (associated to human plasma cell neoplasias) is targeted to mouse B cells, the resulting animals fail to reproduce the human disease. Here, to explore early cellular changes that might take place in the development of plasma cell neoplasias, we engineered transgenic mice to express MafB in haematopoietic stem/progenitor cells (HS/PCs). Unexpectedly, we show that plasma cell neoplasias arise in the MafB-transgenic mice. Beyond their clinical resemblance to human disease, these neoplasias highly express genes that are known to be upregulated in human multiple myeloma. Moreover, gene expression profiling revealed that MafB-expressing HS/PCs were more similar to B cells and tumour plasma cells than to any other subset, including wild-type HS/PCs. Consistent with this, genome-scale DNA methylation profiling revealed that MafB imposes an epigenetic program in HS/PCs, and that this program is preserved in mature B cells of MafB-transgenic mice, demonstrating a novel molecular mechanism involved in tumour initiation. Our findings suggest that, mechanistically, the haematopoietic progenitor population can be the target for transformation in MafB-associated plasma cell neoplasias.     

Genetic polymorphisms in TNFA/TNFR2 genes and Chagas disease in a Colombian endemic population

In this study we investigated the association of functional single nucleotide polymorphisms of tumor necrosis factor-alfa (TNFA) and TNF receptor 2 (TNFR2) genes in determining the susceptibility to Chagas' disease. This study included 313 patients from Colombia serologically positive for Trypanosoma cruzi antigens (cardiomyopathic, N=159; asymptomatic, N=154). Genotypes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism method. We found a significant difference in the distribution of the TNFA -1031C (p=0.0153, OR=1.69, CI=1.10-2.58) and -308A (p=0.0002, OR=2.60, CI=1.53-4.39) alleles between cardiomyopathic and asymptomatic subjects. In addition, we observed that the TNFR2 +676T allele was monomorphic in our population. Our results suggest that TNFA -1031C and -308A gene polymorphisms may influence the susceptibility to develop chagasic cardiomyopathy in the population under study.     

Cardiac and vascular phenotypes in the apolipoprotein E-deficient mouse

Cardiovascular death is frequently associated with atherosclerosis, a chronic multifactorial disease and a leading cause of death worldwide. Genetically engineered mouse models have proven useful for the study of the mechanisms underlying cardiovascular diseases. The apolipoprotein E-deficient mouse has been the most widely used animal model of atherosclerosis because it rapidly develops severe hypercholesterolemia and spontaneous atherosclerotic lesions similar to those observed in humans. In this review, we provide an overview of the cardiac and vascular phenotypes and discuss the interplay among nitric oxide, reactive oxygen species, aging and diet in the impairment of cardiovascular function in this mouse model.     

Senescence-associated proteases in plants

Senescence is the final developmental stage of every plant organ, which leads to cell death. It is a highly regulated process, involving differential gene expression and outstanding increment in the rate of protein degradation. Senescence-associated proteolysis enables the remobilization of nutrients, such as nitrogen (N), from senescent tissues to developing organs or seeds. In addition to the nutrient recycling function, senescence-associated proteases are also involved in the regulation of the senescence process. Nearly, all protease families have been associated with some aspects of plant senescence, and numerous reports addressing the new identification of senescence-associated proteases are published every year. Here, we provide an updated report with the most recent information published in the field, focusing on senescence-associated proteases presumably involved in N remobilization.     

Challenges and Solutions in the Development of Genomic Biomarker Panels: A Systematic Phased Approach

In the post-genome era, high throughput gene expression profiling has been successfully used to develop genomic biomarker panels (GBP) that can be integrated into clinical decision making. The development of GBPs in the context of personalized medicine is a scientifically challenging and resource-intense process. It needs to be accomplished in a systematic phased approach to address biological variation related to a clinical phenotype (e.g. disease etiology, gender, etc.) and minimize technical variation (noise). Here we present the methodological aspects of GBP development based on the experience of the Cardiac Allograft Rejection Gene Expression Observation (CARGO) study, a study that lead to the development of a molecular classifier for rejection screening in heart transplant patients.     

Loss of p53 exacerbates multiple myeloma phenotype by facilitating the reprogramming of hematopoietic stem/progenitor cells to malignant plasma cells by MafB

Multiple myeloma (MM) is a serious, mostly incurable human cancer of malignant plasma cells. Chromosomal translocations affecting MAFB are present in a significant percentage of multiple myeloma patients. Genetically engineered Sca1-MafB mice, in which MafB expression is limited to hematopoietic stem/progenitor cells (HS/P-Cs), display the phenotypic features of MM. Contrary to many other types of cancer, it is not yet known if the p53 gene plays any essential role in the pathogenesis of this disease. Here, we show, taking advantage of the Sca1-MafB MM mouse model, that loss of p53 does not rescue the multiple myeloma disease, but instead accelerates its development and exacerbates the MM phenotype. Therefore, the efficiency of the MafB-induced MM reprogramming of normal HS/P-Cs to terminally differentiated malignant plasma cells is enhanced by p53 deficiency, in analogy to what happens in reprogramming to pluripotency. These results raise caution about interfering with p53 function when treating multiple myeloma.     

Kinetics of the interaction of sulfate and hydrogen phosphate radicals with small peptides of glycine, alanine, tyrosine and tryptophan.

The kinetics and mechanism of the oxidation of Glycine (Gly), Alanine (Ala), Tyrosine (Tyr), Tryptophan (Trp) and some di-(Gly-Gly, Ala-Ala, Gly-Ala, Gly-Trp, Trp-Gly, Gly-Tyr, Tyr-Gly), tri-(Gly-Gly-Gly, Ala-Gly-Gly) and tetrapeptides (Gly-Gly-Gly-Gly) mediated by sulfate (SO(4) (-)) and hydrogen phosphate (HPO(4) (-)) radicals was studied, employing the flash-photolysis technique. The substrates were found to react with sulfate radicals (SO(4) (-), produced by photolysis of the S(2)O(8)(2-)) faster than with hydrogen phosphate radicals (HPO(4) (-), generated by photolysis of P(2)O(8)(4-) at pH = 7.1). The reactions of the zwitterions of the aliphatic amino acids and peptides with SO(4) (-) radicals take place by electron transfer from the carboxylate moiety to the inorganic radical, whereas those of the HPO(4) (-) proceed by H-abstraction from the alpha carbon atom. The phenoxyl radical of Tyr-Gly and Gly-Tyr are formed as intermediate species of the oxidation of these peptides by the inorganic radicals. The radical cations of Gly-Trp and Trp-Gly (at pH = 4.2) and their corresponding deprotonated forms (at pH = 7) were detected as intermediates species of the oxidation of these peptides with SO(4) (-) and HPO(4) (-). Reaction mechanisms which account for the observed intermediates are proposed.     

Collagen-induced arthritis in C57BL/6 mice is associated with a robust and sustained T-cell response to type II collagen

Many genetically modified mouse strains are now available on a C57BL/6 (H-2^b) background, a strain that is relatively resistant to collagen-induced arthritis. To facilitate the molecular understanding of autoimmune arthritis, we characterised the induction of arthritis in C57BL/6 mice and then validated the disease as a relevant pre-clinical model for rheumatoid arthritis.     

Cost-effective HRMA pre-sequence typing of clone libraries; application to phage display selection

Background  

Methodologies like phage display selection, in vitro mutagenesis and the determination of allelic expression differences include steps where large numbers of clones need to be compared and characterised. In the current study we show that high-resolution melt curve analysis (HRMA) is a simple, cost-saving tool to quickly study clonal variation without prior nucleotide sequence knowledge.     

Caffeic Acid Phenylethyl Ester and MG-132 Have Apoptotic and Antiproliferative Effects on Leukemic Cells But Not on Normal Mononuclear Cells

Chemotherapy aims to limit proliferation and induce apoptotic cell death in tumor cells. Owing to blockade of signaling pathways involved in cell survival and proliferation, nuclear factor κB (NF-κB) inhibitors can induce apoptosis in a number of hematological malignancies. The efficacy of conventional chemotherapeutic drugs, such as vincristine (VCR) and doxorubicine (DOX), may be enhanced with combined therapy based on NF-κB modulation. In this study, we evaluated the effect of caffeic acid phenylethyl ester (CAPE) and MG-132, two nonspecific NF-κB inhibitors, and conventional chemotherapeutics drugs DOX and VCR on cell proliferation and apoptosis induction on a lymphoblastoid B-cell line, PL104, established and characterized in our laboratory. CAPE and MG-132 treatment showed a strong antiproliferative effect accompanied by clear cell cycle deregulation and apoptosis induction. Doxorubicine and VCR showed antiproliferative effects similar to those of CAPE and MG-132, although the latter drugs showed an apoptotic rate two-fold higher than DOX and VCR. None of the four compounds showed cytotoxic effect on peripheral mononuclear cells from healthy volunteers. CAPE- and MG-132-treated bone marrow cells from patients with myeloid and lymphoid leukemias showed 69% (P < .001) and 25% decrease (P < .01) in cell proliferation and 42% and 34% (P < .01) apoptosis induction, respectively. Overall, our results indicate that CAPE and MG-132 had a strong and selective apoptotic effect on tumor cells that may be useful in future treatment of hematological neoplasias.