Vincent Sollars | Marshall University (original) (raw)

Papers by Vincent Sollars

Pigment Cell and Melanoma Research, 2010

Mammalian Genome, 2006

The myeloid progenitor cell compartment (MPC) exhibits pronounced expansion in human myeloid leuk... more The myeloid progenitor cell compartment (MPC) exhibits pronounced expansion in human myeloid leukemias. It is becoming more apparent that progression of myelodysplastic syndromes and myeloproliferative diseases to acute myelogenous leukemia is the result of defects in progenitor cell maturation. The MPC of bone marrow was analyzed in mice using a cell culture assay for measuring the relative frequency of proliferative myeloid progenitors. Response to the cytokines SCF, IL-3, and GM-CSF was determined by this assay for the leukemic mouse strain BXH-2 and ten other inbred mouse strains. Significant differences were found to exist among ten inbred mouse strains in the nature of their MPC in bone marrow, indicating the presence of genetic polymorphisms responsible for the divergence. The SWR/J and FVB/J strains show consistently low frequencies of myeloid progenitors, while the DBA/2J and SJL/J inbred strains show consistently high frequencies of myeloid progenitors within the bone marrow compartment. In addition, in silico linkage disequilibrium analysis was conducted to identify possible chromosomal regions responsible for the phenotypic variation. Given the importance of this cell compartment in leukemia progression and the soon to be released genomic sequence of 15 mouse strains, these differences may provide a valuable tool for research into leukemia.

The role of epigenetics in evolution: The extended synthesis

hematopoiesis, stem cells Sollars, Vincent E 2 The new millennium has brought with it a surge of ... more hematopoiesis, stem cells Sollars, Vincent E 2 The new millennium has brought with it a surge of research in the field of epigenetics. This has included advances in our understanding of stem cell characteristics and mechanisms of commitment to cell lineages prior to differentiation. The nature of stem cells is similar to that of malignant cells in that they have unlimited self-renewal and protection from apoptosis, leading researchers to suspect that stem cells are the target of oncogenesis. This review will explore the idea of how epigenetic control of gene expression may contribute to mechanisms controlling differentiation of myeloid progenitor cells and its importance to our understanding of myelogenous leukemias. Recent developments in epigenetic research pertaining to differentiation of myeloid progenitor cells and hematopoietic stem cells are presented including aspects of cellular

License, which permits unrestricted use, distribution, and reproduction in any medium, provided t... more License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Evolutionary biology is currently experiencing an emergence of several research topics that transcend the boundaries of the Modern Synthesis, which was the last major conceptual integration in evolutionary biology [1]. The Modern Synthesis used the concepts of population genetics to integrate Mendelian genetics with evolution by natural selection [2]. Pigliucci [3, and citations within] identified several major areas of innovation that transcend the Modern Synthesis: epigenetics, evolvability, phenotypic plasticity, evolution on adaptive landscapes, evolutionary developmental biology, and systems biology. Integrating these new ideas with the Modern Synthesis will form a new conceptual framework of evolution, which they termed the Extended Synthesis, as it will extend, rather than refute, the Modern Synthesis [3]. Thissubjecthasbeenthefocusofmuchrecentw...

The goal of this study was to ascertain the specific effects of 17-N-Allylamino-17demethoxygeldan... more The goal of this study was to ascertain the specific effects of 17-N-Allylamino-17demethoxygeldanamycin (17-AAG) treatment in human acute myelogenous leukemia (AML). Four human leukemia cell lines were treated with varying doses of 17-AAG followed by analysis of toxicity, apoptosis, proliferation, and cell cycle. Cell cycle analysis revealed that the cells accumulate in G 2 /M phase within 96 hours of treatment, although the effect was not equivalent among the cell lines. p21, p53 expression and MDR1 activity were among the possible mechanisms uncovered for the differing responses. Exploiting these differences may allow for more effective combinatory treatments in patients with AML.

Biomedicine & Pharmacotherapy

OBJECTIVES Despite advances in cancer treatment, drug resistance and metastasis continue to contr... more OBJECTIVES Despite advances in cancer treatment, drug resistance and metastasis continue to contribute to treatment failure. Since drug resistance and metastasis in cancer are features that often occur toward the late stages in the disease after withstanding numerous selective pressures, they may rely on a shared adaptive mechanism in order to persist. The heat shock response is one of the most well conserved adaptive responses to cellular stress found in nature. A major player in the heat shock response is HSP90, with some studies suggesting that it can facilitate the molecular evolution of drug resistance and metastasis in cancer. Non-small cell lung cancers (NSCLCs) are strongly associated with drug resistance and metastasis either at the time of diagnosis or early in the treatment process. MATERIALS AND METHODS We explored the role of HSP90 in the evolution of metastatic and drug resistant features in NSCLC by treating A549 cells with AUY922, a clinically relevant HSP90 inhibitor, and inducing metastatic and drug resistant phenotypes via treatment with TGF-β and paclitaxel, respectively. We measured phenotypic plasticity in E-Cadherin, a marker for epithelial to mesenchymal transition and two ABC transporters associated with drug resistant lung cancers. RESULTS We found that metastatic and efflux dependent drug resistant features negatively correlated with AUY922 treatment. We followed our results with functional assays relevant to metastasis and ABC transporters to confirm our results. Specifically we found the expression of E-cadherin was significantly increased in A549 cultures pretreated with AUY922 prior to exposure to paclitaxel, while expression of the drug transporters ABCB1 and ABCC1 was significantly reduced under similar conditions. CONCLUSION Together our data indicates that HSP90 inhibition with AUY922 can limit the acquisition of metastatic and drug resistant phenotypes in A549 cells at low, clinically appropriate doses.

Cellular reprogramming, Oct 1, 2017

Cancer cells exist in a state of Darwinian selection using mechanisms that produce changes in gen... more Cancer cells exist in a state of Darwinian selection using mechanisms that produce changes in gene expression through genetic and epigenetic alteration to facilitate their survival. Cellular plasticity, or the ability to alter cellular phenotype, can assist in survival of premalignant cells as they progress to full malignancy by providing another mechanism of adaptation. The connection between cellular stress and the progression of cancer has been established, although the details of the mechanisms have yet to be fully elucidated. The molecular chaperone HSP90 is often upregulated in cancers as they progress, presumably to allow cancer cells to deal with misfolded proteins and cellular stress associated with transformation. The objective of this work is to test the hypothesis that inhibition of HSP90 results in increased cell plasticity in mammalian systems that can confer a greater adaptability to selective pressures. The approach used is a murine in vitro model system of hematopoi...

Cancer Research, 2013

The process of canalization whereby phenotypic traits are buffered against stochastic fluctuation... more The process of canalization whereby phenotypic traits are buffered against stochastic fluctuations to preserve the evolutionarily advantageous “normal” level can be potentially exploited during cancer progression. Release of canalization through pharmacologic or genetic down-regulation of Hsp90 removes this buffer and increases variation, allowing for rapid changes in traits as evidenced in Drosophila , Arabidopsis , and maize. If cancer is viewed as a Darwinian struggle of the premalignant cell to acquire the hallmarks of a fully malignant cell or be extinguished, then increasing variation or heterogeneity has a beneficial effect on the fitness of the premalignant cell. It is the goal of this work to test the hypothesis that Hsp90-derived canalization, though its ability to buffer phenotypic variance and thus reduce cell plasticity, is involved in hematopoietic cell differentiation. Furthermore, we wish to determine if the canalization mechanism has an epigenetic component. We are currently using a murine hematopoietic stem cell culture system, EML cells, to investigate this hypothesis. EML cells have been induced to differentiate into macrophage and granulocyte lineages with and without pharmacologic inhibition of HSP90 through 17-AAG. We found that 17-AAG treatment increases the ability of these differentiating cells to survive in a selective medium, during culturing conditions that suggest an epigenetic mechanism. If our hypothesis is true, then loss of canalization could be a potentially powerful mechanism driving cancer progression. Fully understanding the mechanism involved would allow for new therapeutic insights and provide vital information regarding the use of HSP90 inhibitors. Citation Format: Jennifer Napper, Vincent E. Sollars. Phenotypic plasticity in the EML cell culture system as a result of HSP90 inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B16.

Stress-Induced Mutagenesis, 2013

In this chapter, we focus on the role of the chaperone protein Hsp90 as a capacitor for morpholog... more In this chapter, we focus on the role of the chaperone protein Hsp90 as a capacitor for morphological variation that is released during times of stress. Hsp90 helps to fold numerous client proteins, which constitute a veritable "who's who" of important signaling molecules, such as Akt, Raf, Src, chromatinmodifying proteins, nuclear hormone receptors, and kinetochore assembly proteins. We fi rst review evidence that Hsp90 functions trans-generationally as a capacitor for morphological variation via both genetic and epigenetic means: in the former by revealing cryptic genetic variation and in the latter by generating heritable epialleles. Then we discuss two mechanisms by which altered Hsp90 function can mutate DNA: transposon mobilization, and chromosomal aneuploidy. Next, we hypothesize how benefi cial cryptic epigenetic variation might be stabilized, or locked in place, by the directed DNA-level mutation of epigenetically assimilated epialleles. Finally, we describe how Hsp90 functions intra-generationally within an organism's lifetime by releasing cryptic phenotypic variation during development in a stressful environment, and how this can be hijacked during the progression of diseases such as cancer.

Epigenetics protocols, 2004

Quantitative epigenetics (QE) is a new area of research that combines some of the techniques deve... more Quantitative epigenetics (QE) is a new area of research that combines some of the techniques developed for global quantitative trait loci (QTL) mapping analyses with epigenetic analyses. Quantitative traits such as height vary, not in a discrete or discontinuous fashion, but continuously, usually in a normal distribution. QTL analyses assume that allelic DNA sequence variation in a population is partly responsible for the trait variation, and the aim is to deduce the locations of the contributing genes. QE analyses assume that epigenetic variation in a population is partly responsible for the trait variation, and the aim is to associate inheritance of the trait with segregation of informative epigenetic polymorphisms, or epialleles. QTL and QE analyses are thus complementary, but the latter has several advantages. QTL mapping is limited in resolution because of meiotic recombination and population size, placing quantitative traits on genomic regions that are each typically several megabase-pairs long, and requires DNA sequence variation. In contrast, QE analysis can make use of powerful emerging mapping techniques that allow the positioning of epialleles defined by chromatin variation to individual genes or chromosomal regions, even in the absence of DNA sequence variation. In this chapter, we present a case study for QE analysis-epigenetic mapping of enhancers of the KrIf-1 ectopic eye bristle phenotype in an isogenic strain of Drosophila melanogaster.

Nutrition and Cancer from Epdemiology to Biology, 2012

Current Genomics, 2005

Word count: abstract -141, main text -2687

Leukemia Research, 2010

Frontiers in Bioscience, 2005

Immunogenetics, 2011

Hematopoietic transcription factors play a critical role in directing the commitment and differen... more Hematopoietic transcription factors play a critical role in directing the commitment and differentiation of hematopoietic stem cells along a particular lineage. Y-box protein (YBX1) is a transcription factor which is widely expressed throughout development and is involved in erythroid cell development; however, its role in early hematopoietic differentiation is not known. This study aims to investigate the role of YBX1 expression in early hematopoietic differentiation and leukemia. Here, we show that YBX1 is highly expressed in mouse erythroid myeloid lymphoid-clone 1 (EML), a hematopoietic precursor cell line, but is down-regulated in myeloid progenitors and GM-CSF-treated EML cells during the course of myeloid differentiation. Moreover, we found that lineage − /IL-7R − / c-kit + /Sca1 + (LKS; enriched fraction of hematopoietic stem cells) and lineage − /IL-7R − /c-kit + /Sca1 − myeloid progenitor cells showed high level of YBX1 expression as compared to the differentiated cells like granulocytes in mouse bone marrow. Also, YBX1 protein was expressed at high levels in myeloid leukemic cell lines blocked at different stages of myeloid development. We further investigated the role of YBX1 in leukemic cells by knockdown studies and observed that down-regulation of YBX1 expression in K562 leukemic cells inhibited their proliferation ability, induced apoptosis, and differentiation towards megakaryocytic lineage upon arsenic trioxide treatments relative to untreated. Overall, our data indicates that YBX1 is down-regulated during myeloid differentiation and the aberrant YBX1 expression in leukemic cells could be a contributing factor in the development of leukemia by blocking their differentiation. Thus, YBX1 protein could be an excellent molecular target for therapy in myeloproliferative disorders and leukemia.

Human molecular genetics, Jan 15, 2002

We have isolated a Meis1a transgenic mouse line exhibiting recessive male-specific lethality and ... more We have isolated a Meis1a transgenic mouse line exhibiting recessive male-specific lethality and non-alcoholic fatty liver disease (NAFLD), which coincides with pubescence and is androgen-dependent. The phenotype is due to disruption of an endogenous locus, since other Meis1a transgenic lines do not exhibit these phenotypes. Necropsy analysis revealed hepatic microvesicular steatosis in pubescent male homozygous mice, which is absent in transgenic females. The transgene insertion site was localized to chromosome 1 and further refined by cloning the flanking regions. Sequence analysis shows that the integration site disrupts a putative metallo-beta-lactamase gene with a 21.3 kb deletion encompassing exons 5-7.