Expression of TNF receptors and related signaling molecules in the bone marrow from patients with myelodysplastic syndromes

Sawanobori, Masakazu; Yamaguchi, Shuichi; Hasegawa, Maki; Inoue, Miori; Suzuki, Kenshi; Kamiyama, Ryuichi; Hirokawa, Katsuiku; Kitagawa, Masanobu

doi:10.1016/S0145-2126(02)00095-4

« Previous Next »Leukemia Research
Volume 27, Issue 7 , Pages 583-591, July 2003

Expression of TNF receptors and related signaling molecules in the bone marrow from patients with myelodysplastic syndromes

Masakazu Sawanobori
- Department of Pathology and Immunology, Aging and Developmental Sciences, Division of Gerontology and Gerodontology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
- Department of Internal Medicine, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-0012, Japan
Shuichi Yamaguchi
- Department of Pathology and Immunology, Aging and Developmental Sciences, Division of Gerontology and Gerodontology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Maki Hasegawa
- Department of Molecular Pathophysiology, Moleculo-Genetic Sciences, Division of Biomedical Laboratory Sciences, Graduate School of Allied Health Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Miori Inoue
- Department of Pathology and Immunology, Aging and Developmental Sciences, Division of Gerontology and Gerodontology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Kenshi Suzuki
- Department of Internal Medicine, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-0012, Japan
Ryuichi Kamiyama
- Department of Molecular Pathophysiology, Moleculo-Genetic Sciences, Division of Biomedical Laboratory Sciences, Graduate School of Allied Health Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Katsuiku Hirokawa
- Department of Pathology and Immunology, Aging and Developmental Sciences, Division of Gerontology and Gerodontology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Masanobu Kitagawa
- Department of Pathology and Immunology, Aging and Developmental Sciences, Division of Gerontology and Gerodontology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
- Corresponding author. Tel.: +81-3-5803-5399; fax: +81-3-5803-0123.

Received 25 January 2002; accepted 1 June 2002.

Abstract

Myelodysplastic syndromes (MDS) are characterized by peripheral blood cytopenias despite hypercellularity of the bone marrow regarded as the result of ineffective hematopoiesis mainly caused by apoptosis. In this study, we examined the role of tumor necrosis factor (TNF)-induced apoptosis in the bone marrow cells of MDS patients. The constitutive expression of mRNA for TNF receptors (TNFR), including TNFRI and TNFRII, and the adapter molecules, such as the TNF receptor-associated death domain protein (TRADD), Fas-associated death domain protein (FADD), receptor interacting protein (RIP) and TNF receptor-associated factor 2 (TRAF-2) were analyzed by reverse transcriptase (RT)-PCR in bone marrow samples from control, MDS and AML cases. In bone marrow cells from refractory anemia (RA) patients, there was a significant increase in TNFRI expression as compared with control subjects. The expression of TNFRII was also up-regulated in RA cases. In contrast, RA with excess of blasts (RAEB), RAEB in transformation (RAEB-T) and AML cases revealed increased expression of TNFRII, whereas the expression of TNFRI was comparable to control subjects. Immunohistochemical staining revealed that the TNFRI, as well as TNFRII of MDS bone marrow was expressed mainly in hematopoietic cells, but not in macrophage-lineage stromal cells at the protein level. An increased constitutive expression of mRNA for TRADD, FADD and RIP and decreased expression of mRNA for TRAF-2 were observed in bone marrow cells from MDS patients, especially from RA patients, as compared with controls, although the differences were not significant. In many of the AML bone marrow samples, strong expression of TRAF-2 mRNA was marked, while expression levels of other proteins were similar to those in control subjects. These data suggested enhanced signaling by the TNFRI–TRADD–FADD pathway and suppressed signaling by the TRAF-2 pathway in RA. Thus, TNF-α-induced apoptosis may play a role in ineffective hematopoiesis in “early stage MDS” bone marrow, although the regulatory mechanisms for TNF-α-induced signaling would be complicated and not be simply explained only by these pathways.

Keywords: MDS, Bone marrow, Apoptosis, TNF, TNF receptor, Signal transduction