Role of CEBPA mutations in RAS-mediated leukemogenesis
- Role of CEBPA mutations in RAS-mediated leukemogenesis
- Alternative Author(s)
- Issue Date
- 2021. 2
- Oncogenic RAS mutations are critical in inducing several forms of human myeloid leukemia. Previous study has shown that NRASG12D alone is not sufficient to promote malignant tumors. Therefore, I screened several oncogenes (C/EBPα p30, IRX3, and CBFβ-MYH11) that have been known to affect myeloid differentiation for collaboration with NRASG12D in leukemia induction. I confirmed synergistic effect of C/EBPα p30 and NRASG12D combination in in vitro proliferation assay. The transcriptions factor CEBPA (CCAAT/enhancer binding protein α) is crucial for myeloid differentiation and growth arrest. Mutations in the CEBPA genes are found in about 10% of acute myeloid leukemia (AML) patients, and they are mostly biallelic CEBPA mutations. One mutation leads to the frame-shifted mutation at N-terminus (C/EBPα p30) and the other leads to C-terminal point mutations at the basic leucine zipper domain (C/EBPα BRM).
In this study, I investigated three forms of C/EBPα mutations and their combinations for their ability of inducing leukemia in collaboration with NRASG12D. The three C/EBPα mutant forms used in this experiment are p30, BRM2 and dual mutation of p30 and BRM. Among these C/EBPα mutants, p30-BRM dual mutant form, having both C-terminal and N-terminal mutation in a single cistron, showed most potent synergistic effect with NRASG12D. With this system, I analyzed the effect of BRM2 mutation in shifting the transcriptome of leukemic cells in the presence of NRASG12D and I believe the results from this study will offer unique opportunity of understanding the mechanism of the appearance of biallelic C/EBPα mutation in myeloid leukemia patients.
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- GRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원) > BIOMEDICAL SCIENCE(의생명과학과) > Theses (Master)
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