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Tsai dissertation draft 7.6.2017.pdf (6.87 MB)

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Dysregulation of Mitogen-Activated Protein Kinases Signaling and Immune Suppression in B-cell Leukemia

Tsai, Yo-Ting
http://rave.ohiolink.edu/etdc/view?acc_num=osu1499267877187415

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Mutant mitogen-activated protein kinases (MAPK) components-mediated dysregulation of the pathway is commonly exhibited in cancers and can drive malignancies by promoting tumor survival and proliferation. Tumor-mediated immune suppression in both solid tumors and hematologic malignancies is significant and the activated MAPK signaling pathway is evident in solid tumors to enhance immune suppression. The improvement of current therapies in chronic lymphocytic leukemia (CLL) controls disease development to a greater extent, but the leukemia-induced immune suppression remains one of the leading causes of death. The refractory/relapse cases and the severe immune-deficiency provide a strong justification to identify the effect(s) of genetic lesions and to develop strategies to reverse it in CLL. Activating mutation of MAPK components including BRAF occurs in approximately 10% of CLL and nearly 100% of hairy cell leukemia (HCL), and a BRAF pseudogene-mediated MAPK activation presents in up to 30% of B-cell lymphomas. However, the contribution of the mutant BRAF-activated MAPK signaling in B-cell malignancies remains unclear in respects of disease development and tumor-induced immune suppression, and few models of mutant BRAF-mediated MAPK activation are available to address these. We therefore generate both cellular and mouse models of BRAFV600E mutant B-cell leukemia to study these aspects. The work presented here focuses on the evaluation of the pathomechanism of BRAFV600E in B-cell leukemias. Chapter one introduces the background of B-cell development, B-cell receptor (BCR) and MAPK signaling in B-cell malignancies, and MAPK signaling-mediated immune suppression in cancers. In addition, animal models of leukemia with MAPK activation and/or immune suppression are referred. Chapters two evaluates the pathologic effects of BRAFV600E in a CLL cell line, OSUCLL, using a doxycycline transduction manner. We found that transduction of BRAFV600E increases growth rate and enhances activation of OSUCLL cells. Moreover, it leads to changes in transcripts in OSUCLL cells including ABCB1 (aka p-glycoprotein), an ATP-dependent efflux pump and often mediated anti-cancer drug resistance. The mechanism of the ABCB1 induction is evidenced by inhibition of BRAFV600E and MEK kinases using pharmacological agents, and the key mediators are the activated MAPK pathway-induced AP-1 transcription factors. Chapter three introduces a novel mouse model of B-cell leukemia harboring the B-cell restricted BRAFV600E mutation. This new mouse model with B-cell specific BRAFV600E expression was characterized to shorten the leukemia onset and overall survival. The early B-cell development and the proliferation of leukemia B cells were not affected by this mutation. The reduction of B-cell apoptosis and mutant BRAF leukemia-enhanced immune suppression in the microenvironment contributed to the more aggressive disease seen in this B-cell leukemia mouse model. Chapter four concludes the findings, addresses the unanswered questions in this work, and proposes future perspectives, especially the applications of the new mouse model in future preclinical studies. Together, this work, for the first time, employs a transgenic mouse model of B-cell leukemia with B-cell lineage-restricted BRAFV600E expression and demonstrates the immune-suppressive impact of BRAFV600E in B-cell leukemias. Importantly, this mouse model can be utilized to develop rational combination strategies to both directly target the tumor cells and overcome tumor-mediated immune evasion.
John Byrd (Advisor)
146 p.
Biomedical Research; Pharmaceuticals

Recommended Citations

Citations

  • Tsai, Y.-T. (2017). Dysregulation of Mitogen-Activated Protein Kinases Signaling and Immune Suppression in B-cell Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1499267877187415

    APA Style (7th edition)

  • Tsai, Yo-Ting. Dysregulation of Mitogen-Activated Protein Kinases Signaling and Immune Suppression in B-cell Leukemia. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1499267877187415.

    MLA Style (8th edition)

  • Tsai, Yo-Ting. "Dysregulation of Mitogen-Activated Protein Kinases Signaling and Immune Suppression in B-cell Leukemia." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1499267877187415

    Chicago Manual of Style (17th edition)

osu1499267877187415
177
© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.