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Tumor Necrosis Factor and Adiponectin in Bone Marrow Interstitial Fluid from Patients with Acute Myeloid Leukemia Inhibit Normal Hematopoiesis

Authors' Affiliations: ¹ Department of Nutrition, Institute of Basic Medical Research, University of Oslo; ² Department of Hematology, Ullevaal University Hospital, Oslo, Norway; and ³ Department of Biomedicine, Section of Physiology, University of Bergen, Bergen, Norway

Requests for reprints: Per Ole Iversen, Department of Nutrition, Institute of Basic Medical Research, University of Oslo, P.O. Box 1046 Blindern, 0316 Oslo, Norway; E-mail: poiversen{at}hotmail.com.

Purpose: 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.

Experimental Design: 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 (TNF) 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 TNF were unaffected by therapy whereas bone marrow interstitial fluid levels of both cytokines fell significantly in patients entering remission. Transcripts for TNF, 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.

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