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Harnessing the pro-apoptotic function of MYC to improve therapeutic responses in chemoresistant B-cell lymphoma / Colleen Theobald Harrington.
Connect to full text Available online
View online- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Harrington, Colleen Theobald, author.
- Language:
- English
- Subjects (All):
- Cellular biology.
- Molecular biology.
- Oncology.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Local Subjects:
- Cellular biology.
- Molecular biology.
- Oncology.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (120 pages)
- Contained In:
- Dissertations Abstracts International 81-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine. Considerable efforts have been expended toward silencing MYC, which drives many human cancers including Burkitt lymphomas (BL). Yet, the effects of MYC silencing on standard-of-care therapies are poorly understood. Here we found that inhibition of MYC transcription renders B-lymphoblastoid cells refractory to chemotherapeutic agents. This suggested that in the context of chemotherapy, stabilization of Myc protein could be more beneficial than its inactivation. We tested this hypothesis by pharmacologically inhibiting glycogen synthase kinase 3 (GSK-3), which normally targets Myc for proteasomal degradation. We discovered that chemorefractory BL cell lines responded better to doxorubicin and other anti-cancer drugs when Myc was thus stabilized. In vivo, GSK3 inhibitors (GSK3i) enhanced doxorubicin-induced apoptosis in BL patient-derived xenografts (BL-PDX) as well as in murine MYC-driven lymphoma allografts. This enhancement was accompanied by and required deregulation of several key genes acting in the extrinsic, death receptor-mediated apoptotic pathway. Consistent with this mechanism of action, GSK3i also facilitated lymphoma cell killing by a death ligand TRAIL and by a death receptor agonist mapatumumab. Thus, GSK3i synergizes with both standard chemotherapeutics and direct engagers of death receptors and could improve outcomes in patients with refractory lymphomas.
- Notes:
- Source: Dissertations Abstracts International, Volume: 81-08, Section: B.
- Advisors: Thomas-Tikhonenko, Andrei; Committee members: Xiaolu Yang; Chi Dang; Michael Hogarty; Peter Klein.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2019.
- Local Notes:
- School code: 0175
- ISBN:
- 9781392881941
- Access Restriction:
- Restricted for use by site license.
- This item must not be sold to any third party vendors.
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