Fas (CD95) receptor and Fas-ligand expression in bone marrow cells from patients with myelodysplastic syndrome [letter]

Gersuk, GM; Jw, Lee; Beckham, C; Anderson, Jeanne E.; Deeg, H. Joachim

doi:10.1182/blood.v88.3.1122b.1122b

Cited by 39 publications

(9 citation statements)

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“…In the present study we investigated TNF‐α and Fas‐mediated signals and their effect on haemopoiesis in patients with MDS. As suggested by previous reports, results show up‐regulation of TNF‐α ( Yamaguchi et al , 1996 ; Shetty et al , 1996 ), Fas and Fas‐L in the marrow of patients with MDS ( Gersuk et al , 1996 ; Maciejewski et al , 1995a ). In contrast to normal marrow, Fas‐L was also expressed on a proportion of CD34 + precursor cells, as part of the aberrant phenotype of blasts in MDS.…”

Section: Discussionsupporting

confidence: 77%

“…Alternatively, it has been proposed that abnormal expression of negative regulators of haemopoiesis such as TNF‐α may be responsible ( Maciejewski et al , 1995a ; Bogdanovic et al , 1996 ). TNF‐α up‐regulates Fas expression on normal CD34 + haemopoietic precursor cells, and we have shown that both Fas and Fas‐L were up‐regulated on marrow cells from MDS patients ( Gersuk et al , 1996 ). Since Fas‐mediated signals play a central role in apoptosis and Fas signals are triggered by Fas‐L, these findings suggest the possibility that Fas‐mediated apoptosis is involved in haemopoietic failure as observed in patients with MDS.…”

Section: Discussionmentioning

confidence: 93%

“…Although interactions of Fas with Fas‐L have been shown to play a role in the regulation of T‐ and B‐cell development ( Rathmell et al , 1995 ; Dhein et al , 1995 ; Krammer et al , 1994 ; Alderson et al , 1995 ), a role in haemopoiesis is less well defined. Haemopoietic precursors in many patients with MDS express Fas at abnormally high levels ( Gersuk et al , 1996 ; Maciejewski et al , 1995a ; Hatake et al , 1994 ). There is also an increase in Fas‐L expression on MDS marrow cells ( Gersuk et al , 1996 ).…”

mentioning

confidence: 99%

“…Haemopoietic precursors in many patients with MDS express Fas at abnormally high levels ( Gersuk et al , 1996 ; Maciejewski et al , 1995a ; Hatake et al , 1994 ). There is also an increase in Fas‐L expression on MDS marrow cells ( Gersuk et al , 1996 ). Since Fas‐mediated signals play a central role in apoptosis ( Nagata & Golstein, 1995) and Fas signals are triggered by Fas‐Ligand, it is conceivable that Fas‐mediated apoptosis is involved in the haemopoietic failure seen in patients with MDS.…”

mentioning

confidence: 99%

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A role for tumour necrosis factor‐α, Fas and Fas‐Ligand in marrow failure associated with myelodysplastic syndrome

Gersuk

Beckham

Loken³

et al. 1998

Br J Haematol

227

164

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Apoptosis of haemopoietic cells in the marrow of patients with myelodysplastic syndrome (MDS) has been suggested as a mechanism for peripheral cytopenias. We determined the expression of Fas (CD95), Fas‐Ligand (Fas‐L) and TNF‐α factors known to be involved in apoptosis, in the marrow of 44 patients with MDS and characterized their functional relevance in in vitro assays of haemopoiesis. Multidimensional flow cytometry revealed phenotypically aberrant blasts as defined by orthogonal light scatter and CD45 expression in the marrow of 24/44 patients. Among those blasts Fas expression was increased on CD34‐positive cells and on cells co‐expressing HLA‐DR. In addition, Fas‐L was expressed on some CD34+ cells of MDS patients but was never detected on CD34+ cells in normal marrow. Fas and Fas‐L mRNAs as well as mRNA for TNF‐α, known to increase Fas expression in normal marrow, were up‐regulated in patients with MDS. TNF‐α protein and sTNF‐R1 levels in marrow plasma were higher in MDS patients than in controls (P < 0.002 and <0.003, respectively). However, results were dependent upon disease category: TNF‐α levels were significantly higher in patients with refractory anaemia (RA) than in patients with RA with excess blasts (RAEB) or RAEB in transformation (RAEB‐T) (P = 0.043). Conversely, the proportion of Fas‐L‐positive cells was lowest in patients with RA (P = 0.037). In marrow cultures, Fas‐Ig, rhuTNFR:Fc or anti‐TNF‐α antibody, by blocking Fas or TNF mediated signals, respectively, significantly increased the numbers of haemopoietic colonies compared to untreated cells (P < 0.001, P < 0.003, P < 0.001, respectively). These results show significant dysregulation in the expression of TNF‐α, Fas and Fas‐L in the marrow from MDS patients. Altered expression of these molecules appears to be of functional relevance in the dysregulation of haemopoiesis in MDS and may be amenable to therapeutic interventions.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A role for tumour necrosis factor‐α, Fas and Fas‐Ligand in marrow failure associated with myelodysplastic syndrome

Gersuk

Beckham

Loken³

et al. 1998

Br J Haematol

227

164

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“…Although normal erythroid precursors constitutively express fas receptor (CD95), receptor density is low, thereby fostering a high level of resistance to fas ligand-induced apoptosis [11][12][13]. In contrast, in myelodysplastic CD34 + cells, both fas receptor and ligand display are increased, permitting autocrine and paracrine activation of the cell death program [14][15][16][17]. The intensity of CD95 expression on MDS CD34 + cells inversely correlates with blast percentage, whereas fas ligand density remains preserved, indicating that with disease progression, myeloblast populations emerge that are more resistant to fas ligand-induced cell death [16,18].…”

Section: Pathophysiology Of Myelodysplasiamentioning

confidence: 99%