Over-expression of tumor necrosis factor-alpha in bone marrow biopsies from patients with myelodysplastic syndromes: relationship to anemia and prognosis.
OBJECTIVE
An excessive intramedullar progenitor cell apoptosis, to which elevated expression of tumor necrosis factor-alpha (TNF-alpha) might contribute, is considered the main cause of inefficient hematopoiesis in myelodysplastic syndromes (MDS). Enhanced bone marrow (BM) angiogenesis is regarded as an essential cofactor in the progression of MDS to acute myelogenous leukemia (AML) and microvessel formation may be induced by TNF-alpha as well. To investigate TNF-alpha signaling and neoangiogenesis as potential molecular pathways for therapeutic intervention in MDS with respect to the various MDS subtypes, we performed a morphological and clinico-pathological study on a large series of paraffin-embedded trephine BM biopsies.


METHODS
TNF-alpha expression and BM vessels were immunohistochemically analyzed on 89 paraffin-embedded BM biopsies from patients with MDS and secondary AML, including 12 control samples. Data were correlated with clinico-pathological and laboratory parameters and analyzed for their prognostic significance considering overall survival.


RESULTS
TNF-alpha was over-expressed in MDS patients, especially in those with refractory anemia and its expression correlated with BM cellularity and with magnitude of anemia as well as with microvessel density (MVD). TNF-alpha over-expression was associated with premature deaths. MVD was increased in MDS and secondary AML and correlated with marrow cellularity and expression of TNF-alpha, but was not of prognostic significance.


CONCLUSIONS
TNF-alpha expression and MVD are elevated in MDS and secondary AML. TNF-alpha expression in BM progenitor cells appears to negatively impact erythropoiesis and overall survival in MDS, and may serve as a potential therapeutic target in patients with hypercellular MDS with marked anemia.
Stifter
Gerald
G
Division of Hematology and Oncology, Innsbruck Medical University, Innsbruck, Austria.
Heiss
Simone
S
Gastl
Günther
G
Tzankov
Alexandar
A
Stauder
Reinhard
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D001706:Biopsy / Q000379:methods; D001853:Bone Marrow / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D018572:Disease-Free Survival; D015672:Erythroid Precursor Cells / Q000378:metabolism* / Q000473:pathology; D004920:Erythropoiesis; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D014409:Tumor Necrosis Factor-alpha