Multi-Dimensional Suppression of Normal Hematopoietic Cells by MN1-Induced Leukemic Cells = Multi-Dimensional Suppression of Normal Hematopoietic Cells by MN1-Induced Leukemic Cells

다국어 초록 (Multilingual Abstract)

Leukemogenesis comprises engraftment and self-renewal of leukemic stem cells, but also causes insufficiency in normal hematopoietic cells. Here we have investigated the influence of leukemia on various stages of normal hematopoietic functions using meningioma 1 (MN1)-induced acute myelogeneous leukemia model. When normal hematopoietic stem cells (HSCs) were co-transplanted with MN1 leukemia cells, the ability of normal HSCs to execute self-renewal was profoundly suppressed, as demonstrated by lower numbers of competitive repopulating units (CRUs) in the reconstituted bone marrows. The inhibitory effects become more prominent in the competition of leukemic cells for bone marrow niche. Moreover, when normal bone marrow cells were co-cultured with MN1 cells in vitro, the apoptosis of normal bone marrow cells (BMCs) were >2 fold increased, as compared to the culture of normal BMCs alone (p<0.05), whereas MN1 cells in the culture were not affected. The apoptosis of normal BMCs occurred more frequently in the mature myeloid cells than in lineage-negative populations in a manner dependent on direct contact with leukemic cells. Interestingly, the mean survival of leukemia mice was more closely correlated to the extent of bone marrow ablation caused by different dose of radiation to mice than the numbers of leukemic cells transplanted into the irradiated mice. Taken together, our results show that leukemia cells exert inhibitory effects on the multiple stages of normal hematopoiesis, and that such inhibitory influence should play as a key factor in the morbidity of leukemia during the course of illness.