High expression of 67-kDa laminin receptor relates to the proliferation of leukemia cells and increases expression of GM-CSF receptor.

OBJECTIVE: The 67-kDa laminin receptor (LR) is a nonintegrin receptor for laminin, a major component of the extracellular matrix. To elucidate the role of LR in leukemia cells, we studied the relationship between the phenotype of leukemia cells and LR expression. MATERIALS AND METHODS: The relationship between clinical features of acute myeloid leukemia and expression of LR was examined. LR was overexpressed or suppressed by the introduction of complementary DNA or small interfering RNA for LR in a human leukemia cell line to test the effect of LR on the phenotype of leukemia. Expression of granulocyte-macrophage colony-stimulating factor receptors (GM-CSFR) was also tested in leukemia cells, including clinical samples. RESULTS: Expression of LR was significantly related to elevation of white blood cell count, lactate dehydrogenase, and survival among acute myeloid leukemia patients. Forced expression of LR enhanced proliferation, cell-cycle progression, and antiapoptosis of leukemia cells associated with phosphorylation of a transcription factor, signal transducer and activator of transcription 5, in the absence of stimulation by laminin. On the other hand, suppression of LR expression had the opposite effects. The number of GM-CSFR increased in leukemia cells overexpressing LR, and there was a significant relationship between the expression of LR and GM-CSFR in acute myeloid leukemia samples. CONCLUSIONS: These results suggest that LR expression influenced the characteristics of leukemia cells toward an aggressive phenotype and increased the number of GM-CSFR. These changes might be partly related to enhanced GM-CSF signaling.

Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group.

Imatinib has dramatically improved long-term survival of chronic myelogenous leukemia (CML) patients. To analyze its efficacy in a practical setting, we registered most of CML patients in Nagasaki Prefecture of Japan. Of these, 73 patients received imatinib as an initial therapy. The overall survival rate of these patients was 88.7% at 6 years, and the cumulative complete cytogenetic response rate was 82.5% at 18 months. These results are comparable with the data of other reports including the IRIS study; however, the administered imatinib dose was smaller in our study than that in other reports. To address these discrepancies, we measured the trough concentration of imatinib among 35 patients. Although 39% of the patients were administered less than 400 mg/day, the trough level was comparable to those of previous reports. The trough level of imatinib showed a significant relationship with its efficacy, and was clearly related to dose of imatinib administrated and dose of imatinib divided by body surface area (BSA). Considering the smaller BSA of Japanese patients as compared to those of foreign origin, the results suggest that a lower dose of imatinib could maintain enough trough level and provided excellent results for the treatment of CML in our registry.