The role of Pyruvate Kinase M2 in Chronic myelogenous Leukemia progression
碩士 === 國立陽明大學 === 醫學生物技術暨檢驗學系 === 104 === Chronic myelogenous leukemia (CML) is a type of cancer that begins in certain bone marrow blood-forming cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulati...
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| Format: | Others |
| Language: | en_US |
| Published: |
2016
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| Online Access: | http://ndltd.ncl.edu.tw/handle/52516784838481385354 |
| Summary: | 碩士 === 國立陽明大學 === 醫學生物技術暨檢驗學系 === 104 === Chronic myelogenous leukemia (CML) is a type of cancer that begins in certain bone marrow blood-forming cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood. We used the gene set enrichment analysis (GSEA) study and found an important glycolytic enzyme, Pyruvate kinase M2 (PKM2) that regulates the gene pattern and is correlated with the leukemia stem cell (LSC) population (Lin- CD34 -/+) in CML microarray result. PKM2 is a glycolytic enzyme for metabolism and the nuclear function for cancer progression. We therefore focus on studying the role of PKM2 in CML progression. We generated a PKM2 knockdown cell-line and found that the loss of PKM2 decreases CML cell clonogenic potential and promotes erythrocytic differentiation in K562 cells. Next we determined the critical signal for PKM2 nuclear localization in CML. Using inhibitor and cytokine screening results we found that BCR-ABL and STAT5 are important activation signals to induce PKM2 nuclear localization. We then used the GSEA study and found that serine proteinase inhibitor Kazal-type 2 (SPINK2) is one of the core enrichment genes in LSC signature and PKM2 regulated gene sets. SPINK2 knockdown in CML cells also decreases colongenic potential. We finally performed the chromatin immunoprecipitation (ChIP) assay and found that PKM2 and STATs occupied the SPINK2 promoter. Collectively, these results demonstrate that the CML dominant signal BCR-ABL-STAT5 plays a role in PKM2 nuclear localization. We also found that nuclear PKM2 and STATs may collaboratively drive gene expression including SPINK2 for CML progression.
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