Common Dietary and Environmental Compounds Promote a Leukemic Translocation in Hematopoietic Stem Cells and Differentiated Cells

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Vestal, C. (2016). Common Dietary and Environmental Compounds Promote a Leukemic Translocation in Hematopoietic Stem Cells and Differentiated Cells. Unc Charlotte Electronic Theses And Dissertations.
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Abstract

Maternal exposure to topoisomerase II (topoII) inhibitors that are biochemically similar to the chemotherapeutic drug etoposide may promote infant acute leukemia. Several studies have shown that common dietary bioflavonoids as well as benzene metabolites can induce DNA double strand breaks (DSB) and inhibit topoII. The goal of this study was to determine the relative potential for bioflavonoids genistein and quercetin, and possible leukemogenic compounds p-benzoquinone and dipyrone to promote rearrangements between the MLL and AF9 breakpoint cluster regions within specific hematopoietic cell subpopulations. A murine embryonic stem (ES) cell line containing two Green Fluorescent Protein (GFP) DSB-inducible recombination reporter substrates was differentiated in vitro into embryoid bodies (EB) containing hematopoietic stem cells (HSC) followed by differentiation into myeloid progenitor subpopulations. Following exposure to genistein, quercetin, p-benzoquinone, or dipyrone at each of three developmental stages, the frequency of interchromosomal translocations between the MLL-AF9 bcrs was determined as well as the mechanism used for repair. Bioflavonoids genistein and quercetin were the strongest inducers of translocations during the earliest stage of differentiation. The frequency of translocations induced by each of these compounds at later stages of differentiation was dramatically reduced. The results demonstrate that all four compounds promote translocations between the MLL and AF9 bcrs at different stages of differentiation and ES cells are particularly susceptible.

Details
Author

Vestal, Carol

Title

Common Dietary and Environmental Compounds Promote a Leukemic Translocation in Hematopoietic Stem Cells and Differentiated Cells

Physical Description

1 online resource (269 pages) : PDF

Date

2016

Degree Granting Institution

University of North Carolina at Charlotte

Abstract

Maternal exposure to topoisomerase II (topoII) inhibitors that are biochemically similar to the chemotherapeutic drug etoposide may promote infant acute leukemia. Several studies have shown that common dietary bioflavonoids as well as benzene metabolites can induce DNA double strand breaks (DSB) and inhibit topoII. The goal of this study was to determine the relative potential for bioflavonoids genistein and quercetin, and possible leukemogenic compounds p-benzoquinone and dipyrone to promote rearrangements between the MLL and AF9 breakpoint cluster regions within specific hematopoietic cell subpopulations. A murine embryonic stem (ES) cell line containing two Green Fluorescent Protein (GFP) DSB-inducible recombination reporter substrates was differentiated in vitro into embryoid bodies (EB) containing hematopoietic stem cells (HSC) followed by differentiation into myeloid progenitor subpopulations. Following exposure to genistein, quercetin, p-benzoquinone, or dipyrone at each of three developmental stages, the frequency of interchromosomal translocations between the MLL-AF9 bcrs was determined as well as the mechanism used for repair. Bioflavonoids genistein and quercetin were the strongest inducers of translocations during the earliest stage of differentiation. The frequency of translocations induced by each of these compounds at later stages of differentiation was dramatically reduced. The results demonstrate that all four compounds promote translocations between the MLL and AF9 bcrs at different stages of differentiation and ES cells are particularly susceptible.

Genre

doctoral dissertations

Subjects--Topics

Molecular biology
Biology
Genetics

Degree

Ph.D.

Keywords

Acute Myeloid Leukemia
Bioflavonoids
Chromosomal Translocations
Environmental Toxicology
Genome Instability
Topoisomerase II

Subject Area

Biology

Advisor(s)

Richardson, Christine

Committee Members

Marriott, Ian
Dreau, Didier
Yan, Shan
Gibas, Cynthia

Degree Note

Thesis (Ph.D.)--University of North Carolina at Charlotte, 2016.

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Rights Holder Information

Copyright is held by the author unless otherwise indicated.

Identifier

Vestal_uncc_0694D_11064

Permalink

http://hdl.handle.net/20.500.13093/etd:225