| Summary: | 碩士 === 國立臺灣大學 === 醫事技術學研究所 === 91 === Normal bone marrow contains hematopoietic stem cells that give rise to peripheral blood cells. Immature hematopoietic cells are normally entrapped in the bone marrow (BM) by a putative “marrow- blood barrier” (MBB). Only after differentiation into mature ones can they leave BM to peripheral blood (PB). In PBSC（Peripheral blood stem cell） transplantation, G-CSF can stimulate hematopoietic progenitor cells in BM to egress through MBB to PB in donor. This process is called mobilization. The transplanted PB progenitor cells then can go into the BM of recipient, and this process is called homing. However, leukemic cells easily pass through MBB without external stimulation. The mechanisms responsible for this phenomenon are largely unknown. The recent discovery of specific interaction of chemokine receptor- CXCR4 with its ligand- CXCL12 has shed light on this important issue, and we want to know more about it.
There are 2 parts of our study. In the first part, we investigate the CXCR4/CXCL12 interaction in leukemic cell lines. And in the second part, blood cells of patients with AML and ALL are evaluated.
Among 6 leukemic cell lines in our study, two (Raji, HL-60) that contain CXCR4 failed to interact with CXCL12. We demonstrated that dysfunction of CXCR4/CXCL12 in Raji cell line was caused by defect in internalization that interrupted CXCR4/CXCL12 signaling pathway. At the same time, we also observed that HL-60 cell line had the defect in CXCR4/CXCL12 signaling pathway, although there was perfect function of internalization. Comparing to other leukemic cell lines, the K562 and HL-CZ leukemic cell lines, which did not express CXCR4 on cell surface, had lower level of CXCR4 mRNA but still had substantial intracellular CXCR4 protein. Therefore, we hypothesized that the CXCR4 expression of K562 and HL-CZ cells somehow was inhibited in transcriptional level and then influenced the process of CXCR4 protein synthesis.
In 13 AML patients we studied last year, we found that immature cells in PB had higher rates of spontaneous migration than immature cells in bone marrow. Six of the 13 patients, whose immature hematopoietic cells in bone marrow expressed higher amount CXCR4 on cell surface, had less immature cell counts in the peripheral blood. This less accumulation of immature cells in PB was caused by higher CXCL12 concentration in BM plasma.
In conclusion, we hypothesized that the accumulation of immature cells in PB of patients with AML was caused by both the characteristics of the cells themselves, and the variation in microenvironments of BM and PB. In our study of patients with ALL, however, we needed more newly diagnosed patients to investigate the importance of interaction of CXCR4/CXCL12.
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