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The activation of Racl GTP enzyme on leukemia cells in the bone marrow microenvironment in detention and in maintaining dry effect

Author: YuPei
Tutor: RaoQing
School: Beijing Union Medical College
Course: Cell Biology
Keywords: Rac1GTPase leukemia cell quiescence homing chemotherapy resistance
CLC: R733.7
Type: Master's thesis
Year: 2012
Downloads: 15
Quote: 0
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Abstract


Objective:To study the role of Racl GTPase activation in the regulation of cell cycle, chemotherapy resistance and homing of leukemia cells.Methods:The lentivirus vector carrying cDNA of constitutively active Rac1or dominant negative Racl and the empty lentivirus vector were constructed and infected into KG la cells respectively. Apoptosis in three sorts of KGla cells was induced by incubating with VP16and was detected in24h and48h. The difference of GO phase ratio in these three sorts of KGla cells were detected by flow cytometry. After4days dealing with KGla cells by NSC23766, the Racl-specific inhibitor, the ratio of GO phase change was also detected. These three sorts of KGla cells were then respectively injected into sublethal NOD/SCID mice through tail vein, and the homing ability was after16h. The location of KGla cells in bone marrow was observed by immunostaining technique with optical microscope. The different transcription level of the genes associated with cell cycle in three sorts of KG1a cells was detected by Real Time PCR, and expression level of these molecules was detected by immunofluorescence and confocal microscopy.. Followed by co-cultured with osteoblast cells, the GO phase ratio and apoptosis induced by VP16of three sorts of KG1a cells were detectedResults:The early or late apoptosis which was induced by incubating with VP16for24h or48h, was obviously higher in dominant negative Racl lentiviral vector infected KGla cells (Rac1-N17-KG1a) than that in constitutively active Rac1lentiviral vector infected KGla cells (Racl-V12-KGla)(P<0.05). The GO phase ratio of (Rac1-V12-KG1a) cell was highest, while that of Racl-N17-KGla cells was lowest, and the difference of GO phase ratio was significant (P<0.05). The GO phase ratio of the KGla deal with Racl-specific inhibitor decreased significantly (P<0.05) as concentration of NSC23766increase. The homing capability of Rac1-V12-KG1a cells was significantly higher than that of Rac1-N17-KG1a cells (P<0.05), and KGla cells were located in osteoblast region in bone marrow. Detected by Real Time PCR, the mRNA transcription level of N-Cadherin, Tie-2and c-MPL was significantly higher in Rac1-V12-KG1a cells than that in Racl-N17-KG1a cells (P<0.05), and the protein expression level of these genes observed by confocal microscopy was consistent with their mRNA transcription level. After co-cultured with osteoblast cells, the GO ratio of three sorts of KGla cells were similar with before, but the GO ratios were all higher significantly than before.Conclusion:By up-regulating the expression of N-Cadherin, Tie-2and c-MPL, the activation of Racl GTPase could enhance the homing capability of leukemia cells, increase the ratio of quiescent cells, and result in chemotherapy resistance; Rac1GTPase can also increase the ratio of quiescent cells directly, and enhance chemotherapy resistance.

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CLC: > Medicine, health > Oncology > Hematopoietic and lymphoid neoplasms > Leukemia
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