| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Research Abstract |
We reported that PU.1 is down-regulated in primary myeloma cells of some patients and most of myeloma cell lines whereas PU.1 is expressed in normal plasma cells. We conditional expressed PU.1 in myeloma cell lines, U266 and KMS12PE, and found that PU.1 induced growth arrest and apoptosis in both cell lines, suggesting that down-regulation of PU.1 is necessary for myeloma cell growth. To elucidate the mechanisms of growth arrest and apoptosis, we performed DNA microarray analysis to compare the gene expressions between before and after PU.1 induction. Among apoptosis related genes, TRAIL is highly up-regulated in both U266 and KMS12PE cells, while among cell cycle related genes, p21^<WAF1/CIP1> is up-regulated in only in U266 cells. Stably expressed siRNA for TRAIL inhibited apoptosis of highly PU.1-expressing U266 and KMS12PE cells, suggesting that TRAIL may have a crucial role in the PU.1- induced apoptosis. In addition, stably expressed siRNA for p21^<WAF1/CIP1> partially rescued U266 cells expressing PU.1 from growth arrest, suggesting that the growth arrest of U266 cells induced by PU.1 should be at least in part dependent on p21^<WAF1/CIP1> up-regulation.
It has been reported that in classical Hodgkin lymphoma cells, PU.1 is also down-regulated through methylation of its promoter. To evaluate whether down-regulation of PU.1 is necessary for growth of classical Hodgkin lymphoma cells, we also conditionally expressed PU.1 in two classical Hodgkin lymphoma cell lines, L428 and KMH2, using the tet-off system. Up-regulation of PU.1 induced growth arrest and apoptosis of L428 and KMH2 cells. Thus, up-regulation of PU.1 by demethylation agents and/or HDACI might serve as a possible treatment modality for multiple myeloma and classical Hodgkin lymphoma.
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