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An rna-interaction domain screen identifies ptbp1 as a dependency in kmt2a-rearranged acute myeloid leukemia Kurtis N McCannell
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- McCannell, Kurtis N., author.
- Language:
- English
- Subjects (All):
- Genetics.
- Oncology.
- Cellular biology.
- Molecular biology.
- 0369.
- 0992.
- 0379.
- 0307.
- Local Subjects:
- Genetics.
- Oncology.
- Cellular biology.
- Molecular biology.
- 0369.
- 0992.
- 0379.
- 0307.
- Genre:
- Academic theses
- Physical Description:
- 1 online resource (123 pages)
- Contained In:
- Dissertations Abstracts International 87-12B
- Place of Publication:
- Ann Arbor : ProQuest Dissertations and Theses, 2026
- Language Note:
- English
- Summary:
- Cancer develops from the acquisition of genetic mutations that re-wire the cells' gene regulatory networks to utilize alternative molecular pathways that support unrestrained proliferation and survival. A critical component of protein-coding gene regulation involves the processing of RNAs to modify their stability, localization, and utilization in the cell, as well as their sequence itself through RNA splicing. Many genes involved in these processes have been identified as vulnerabilities in specific varieties of cancer, leading to novel drug development to improve patient outcomes. To expand on these results, we systematically surveyed a broad spectrum of human cancer cell lines by performing domain-focused CRISPR screens targeting all known RNA-interacting protein genes. These screens identified acute myeloid leukemia (AML) dependencies, including the splicing factor gene PTBP1, with a bias toward KMT2A-rearranged (KMT2A-r) AML, an aggressive subtype with poor clinical outcomes. Genetic and cellular validation confirmed all four RNA-binding domains in PTBP1 are required for KMT2A-r AML proliferation. PTBP1 loss led to cell cycle arrest, apoptosis, and induction of myeloid differentiation. Transcriptomic analyses revealed widespread dysregulation of gene expression and splicing. eCLIP-seq further showed that PTBP1 binds to a subset of these transcripts critical for AML proliferation, including FLT3, BCL2, IKZF1, and MEF2C. Our findings demonstrate that PTBP1 supports AML proliferation by fine-tuning the expression and splicing of AML-essential genes, and our screen design provides a workflow for systematically annotating RNA enzyme and RNA-binding protein dependencies in cancer
- Notes:
- Source: Dissertations Abstracts International, Volume: 87-12, Section: B.
- Includes supplementary digital materials
- Advisors: Shi, Junwei Committee members: Choi, Peter S.; Bernt, Kathrin M.; Gardini, Alessandro; Wan, Liling
- Ph.D. University of Pennsylvania 2026
- Vendor supplied data
- Local Notes:
- School code: 0175
- ISBN:
- 9798247979968
- Access Restriction:
- Restricted for use by site license
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