Tumor necrosis factor alpha and adiponectin in bone marrow interstitial fluid from patients with acute myeloid leukemia inhibit normal hematopoiesis.
OBJECTIVE
Locally residing cytokines may inhibit bone marrow hematopoiesis in acute myeloid leukemia (AML). Using a novel method to isolate bone marrow interstitial fluid, we examined if this fluid from 10 adult AML patients could affect normal bone marrow hematopoiesis.


METHODS
Bone marrow interstitial fluid was isolated by centrifugation of bone marrow biopsies obtained at time of diagnosis and 2 to 4 weeks after start of induction therapy. The isolated fluid was added to normal bone marrow CD34 hematopoietic progenitor cells sampled from five healthy subjects.


RESULTS
Unlike plasma, AML-derived bone marrow interstitial fluid clearly repressed hematopoietic progenitor cell growth as determined by an in vitro colony assay, an effect that was lost after successful induction treatment. Antibodies against tumor necrosis factor alpha (TNFalpha) and adiponectin abolished growth inhibition by bone marrow interstitial fluid, suggesting a mechanistic role of these cytokines in impairing normal hematopoiesis in AML. The plasma levels of adiponectin and TNFalpha were unaffected by therapy whereas bone marrow interstitial fluid levels of both cytokines fell significantly in patients entering remission. Transcripts for TNFalpha, but not for adiponectin, were found in AML blast cells. Neither the plasma levels nor the bone marrow interstitial fluid levels of the proangiogenic factors vascular endothelial growth factor or basic fibroblast growth factor were appreciably elevated in the patients nor did they change with treatment.


CONCLUSIONS
Specific analyses of bone marrow interstitial fluid may give novel information on normal and malignant hematopoietic activity and thus form the basis for mechanism-based therapy.
Iversen
Per Ole
PO
Department of Nutrition, Institute of Basic Medical Research, University of Oslo, Norway. poiverson@hotmail.com
Wiig
Helge
H
D052242:Adiponectin / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000096:biosynthesis; D001706:Biopsy; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002498:Centrifugation; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006413:Hematopoietic System; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D012074:Remission Induction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D052242:Adiponectin; D018952:Antigens, CD34; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha