Mortensen B T, Jensen P O, Helledie N, Iversen P O, Ralfkiaer E, Larsen J K, Madsen M T
Haematology Laboratory Department L, Herlev Hospital, Copenhagen, Denmark.
Br J Haematol. 1998 Jul;102(2):458-64. doi: 10.1046/j.1365-2141.1998.00801.x.
The Brown Norwegian rat transplanted with promyelocytic leukaemic cells (BNML) has been used as a model for human acute myeloid leukaemia. We have previously shown that both the blood supply to the bone marrow and the metabolic rate decrease in relation to the leukaemic development in these rats. Here we have investigated how the development and progression of this leukaemia affect oxygenation, pH and proliferation of normal and leukaemic cells in vivo. Bone marrow pH was measured by a needle electrode. Nitroimidazol-theophylline (NITP) was used to identify hypoxic cells, and we applied bromodeoxyuridine (BrdUrd) to identify DNA replicating cells. The leukaemia progressed slowly until day 27 after which a rapid deterioration could be observed leading to severe changes over the following 5 d. In whole blood there was evidence of progressing metabolic acidosis. In bone marrow the fraction of leukaemic cells increased to > 90% and the pH dropped to about 6.5. The fraction of NITP+ cells increased to > 80% in bone marrow and to about 40% in blood. The fraction of BrdUrd+ cells was unchanged in blood, but decreased in bone marrow both for normal cells (from about 20% to 5%), and for leukaemic cells (from about 45% to 25%), evidently as a result of the severely changed microenvironment. In this study we have demonstrated in vivo the development of an acidic and hypoxic bone marrow hampering normal haemopoiesis during leukaemic growth. Our data support the notion of BNML as a valuable tool for studying leukaemogenesis.
移植了早幼粒细胞白血病细胞（BNML）的挪威棕色大鼠已被用作人类急性髓系白血病的模型。我们之前已经表明，在这些大鼠中，骨髓的血液供应和代谢率均随着白血病的发展而降低。在此，我们研究了这种白血病的发展和进展如何影响体内正常细胞和白血病细胞的氧合、pH值及增殖。通过针电极测量骨髓pH值。使用硝基咪唑 - 茶碱（NITP）来识别缺氧细胞，并应用溴脱氧尿苷（BrdUrd）来识别DNA复制细胞。白血病进展缓慢，直至第27天，之后可观察到快速恶化，在接下来的5天内导致严重变化。全血中有代谢性酸中毒进展的证据。在骨髓中，白血病细胞比例增加至> 90%，pH值降至约6.5。骨髓中NITP +细胞比例增加至> 80%，血液中约为40%。BrdUrd +细胞比例在血液中未发生变化，但在骨髓中，正常细胞（从约20%降至5%）和白血病细胞（从约45%降至25%）均下降，显然是由于微环境严重改变所致。在本研究中，我们在体内证明了白血病生长过程中酸性和缺氧骨髓的形成，这会阻碍正常造血。我们的数据支持BNML作为研究白血病发生的有价值工具这一观点。
