TY - JOUR

T1 - Changing bone marrow micro-environment during development of acute myeloid leukaemia in rats

AU - Mortensen, B T

AU - Jensen, P O

AU - Helledie, N

AU - Iversen, P O

AU - Ralfkiaer, E

AU - Larsen, J K

AU - Madsen, M T

PY - 1998/7

Y1 - 1998/7

N2 - 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.

AB - 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.

KW - Acute Disease

KW - Animals

KW - Body Weight

KW - Bone Marrow

KW - Cell Cycle

KW - Hematopoiesis

KW - Hydrogen-Ion Concentration

KW - Leukemia, Myeloid

KW - Leukemia, Promyelocytic, Acute

KW - Leukocyte Count

KW - Liver

KW - Male

KW - Neoplasm Seeding

KW - Nitroimidazoles

KW - Organ Size

KW - Oxygen Consumption

KW - Radiation-Sensitizing Agents

KW - Rats

KW - Rats, Inbred BN

KW - Spleen

KW - Theophylline

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

M3 - Journal article

C2 - 9695960

VL - 102

SP - 458

EP - 464

JO - British Journal of Haematology

JF - British Journal of Haematology

SN - 0007-1048

IS - 2

ER -