1 option
Dissection of Transcriptional Vulnerabilities in Acute Myeloid Leukemia / Bianca Ysabel Higwit Pingul.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Pingul, Bianca Ysabel Higwit, author.
- Language:
- English
- Subjects (All):
- Biology.
- Genetics.
- Biochemistry.
- Oncology.
- Biochemistry and Molecular Biophysics--Penn dissertations.
- Penn dissertations--Biochemistry and Molecular Biophysics.
- Local Subjects:
- Biology.
- Genetics.
- Biochemistry.
- Oncology.
- Biochemistry and Molecular Biophysics--Penn dissertations.
- Penn dissertations--Biochemistry and Molecular Biophysics.
- Physical Description:
- 1 online resource (146 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by uncontrolled self-renewal and blocked differentiation of myeloid precursor cells. Some of the recurrent oncogenic alterations in AML involve transcription factors (TFs) and epigenetic regulators, which ultimately aid in the augmentation of transcriptional dysregulation and malignant transformation. However, one caveat to consider is that the heterogeneity of the molecular subtypes driving AML pathogenesis makes it challenging to develop targeted therapeutics. One such approach to bypass this predicament in expanding effective therapeutic strategies is to identify non-oncogenic TF dependencies that AML exploits. These dependencies are generally not mutated but are required to maintain AML regulatory programs. Thus, we can identify and utilize these vulnerabilities as selective therapeutic targets for AML with varying subtypes.In this thesis, I leveraged the clustered regulatory interspaced short palindromic repeats (CRISPR) toolbox and molecular biology techniques to investigate the mechanism of a unique transcriptional circuit dependency in AML. Previously, a TF-focused CRISPR screen conducted has identified Myocyte Enhancer Factor 2D (MEF2D) as a selective dependency for AML with distinct molecular subtypes and high MEF2D expression. Herein, we validated this finding through genetic perturbation of MEF2D in AML and show that MEF2D is required in a subset of AML. Thus, we sought to investigate its functional role in transcriptional dysregulation. First, we determined the transcriptomic effects of MEF2D by performing RNA-seq and discovered that perturbation of MEF2D downregulates another identified AML-TF dependency Interferon Regulatory Factor 8 (IRF8). Upon inspection of whether these two have a transcription association, we found that MEF2D and IRF8 have a high correlation of expression levels and requirement for proliferation in cancer patients. Beyond this, we delineated the transcriptional circuitry between MEF2D and IRF8 and their association with PU.1, and further explored the convergent and divergent functionalities of these two TFs in AML. Together, our work dissected the role of MEF2D as a vulnerability in AML and uncovered its novel cooperation with IRF8 and PU.1 to form an interconnected regulatory network that sustains transcriptional programs required for AML survival.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Shi, Junwei; Committee members: Gardini, Alessandro; Bernt, Kathrin M.; Conn, Crystal S.
- Department: Biochemistry and Molecular Biophysics.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381472110
- Access Restriction:
- Restricted for use by site license.
The Penn Libraries is committed to describing library materials using current, accurate, and responsible language. If you discover outdated or inaccurate language, please fill out this feedback form to report it and suggest alternative language.