PHF6 modulates the chromatin landscape in B-cell leukemia
Name
1036985757-MIT.pdf
Description
Full printable version
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30.05 MB
Format
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Checksum (MD5)
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Author(s)
Bartlebaugh, Jordan Michael Elizabeth
Advisor(s)
Michael T. Hemann.
Alternative Title
Plant Homeodomain Finger Protein 6 modulates the chromatin landscape in B-cell leukemia
Date Issued
2018
Publisher
Massachusetts Institute of Technology
Abstract
Developmental and lineage plasticity have been observed in numerous malignancies, and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the Plant Homeodomain Finger Protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B- and T-cell specific factors. Additionally, Phf6KO cells show significant down-regulation of genes involved in the development and function of normal B-cells, up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity, and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition.
Description
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Subjects
Biology.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
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