Type
Text
Type
Dissertation
Advisor
Senthil K. Muthuswamy | Korach, Chad S. | Linda Van Aelst | Nakamura, Toshio | Ute M. Moll | Kevin Shannon.
Date
2010-05-01
Keywords
Biology, Genetics -- Biology, Cell -- Biology, Molecular | Acute Myeloid Leukemia, MEK inhibition, p53, Ras signaling, Self-renewal, Spry4
Department
Department of Genetics
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/72732
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Acute myeloid leukemia (AML) is the major form of adult acute leukemia. It is characterized by colonial expansion of malignant myeloid progenitors in bone marrow, resulting in insufficient generation of normal blood components to cause sever infection, fatigue, and hemorrhage in patients. p53 is a tumor suppressor that commonly mutates in human cancers. p53 mutations have profound effects on AML biology and are associated with the clinical aggressiveness and drug resistance. However, how p53 loss influences AML development remains to be determined. Mouse models recapitulating molecular alterations of human cancer are useful tools to dissect the in vivo roles of tumor suppressor genes and understand pathophysiology process of tumorogenesis. In my Ph.D. dissertation study, I established a mouse model of AML with p53 deficiency and oncogenic Kras activation (Kras-shp53). By exploiting well-established assays to assess self-renewal capabilities of normal and leukemic cells, I found that p53 deficiency provides one mechanism whereby committed myeloid progenitor cells acquire the capacity for indefinite self-renewal, which contributes to leukemogenesis. I also established that Kras-shp53 leukemic cells exhibit constitutive activation of Ras signaling and found that suppression of Spry4 gene (one of the negative regulators of Ras signaling) cooperates with Kras activation to induce leukemia/lymphoma. Finally, I established that p53 status determines the level of Ras signaling flux and predisposes the leukemias to differential responsiveness to MEK inhibition. All in all, my work has provided new insights into p53 tumor suppressive actions and AML biology, and has lead to design of better therapeutic strategies.
Recommended Citation
Zhao, Zhen, "p53 Action in Suppressing Acute Myeloid Leukemia" (2010). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 1935.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/1935