Disease-related anemia in chronic lymphocytic leukemia is not due to intrinsic defects of erythroid precursors: a possible pathogenetic role for tumor necrosis factor-alpha.
OBJECTIVE
Disease-related anemia in chronic lymphocytic leukemia (CLL) occurs when the obvious causes are excluded while its pathogenesis is still obscure. We investigated its underlying mechanisms in 56 untreated patients with CLL.


METHODS
Bone marrow (BM) lymphocytic infiltration was estimated in trephine biopsies. Serum erythropoietin (EPO) and tumor necrosis factor-alpha (TNF-alpha) levels were measured by ELISA. The potential of BM CD34+ to differentiate into erythroid cells was evaluated by methylcellulose-based assays and in liquid cultures supplemented with EPO, SCF, IL-3 +/- TNF-alpha. The response of erythroid precursors to EPO +/- TNF-alpha was assessed by detecting activated key proteins of EPO-EPO receptor signalling pathway using Western Blot and EMSA.


RESULTS
Bone marrow lymphocytic infiltration was not exclusively responsible for disease-related anemia and CD34+ cells were intrinsically capable of generating erythroid precursors. Also, no deficiency of serum erythropoietin (EPO) or defective intracellular response of erythroid precursors to EPO +/- TNF-alpha stimulation was observed. Serum TNF-alpha levels were found increased in anemic CLL patients and TNF-alpha appeared to directly inhibit the erythroid development in early stages of erythropoiesis.


CONCLUSIONS
We concluded that CLL-related anemia was not due to intrinsic defects of erythroid precursors, but might result from the direct suppressive effect of TNF-alpha on the erythroid production.
Tsopra
Olga A
OA
Department of Internal Medicine, Hematology Division, University Medical School of Patras, Patras, Greece. olgatsopra@hotmail.com
Ziros
Panos G
PG
Lagadinou
Eleni D
ED
Symeonidis
Argiris
A
Kouraklis-Symeonidis
Alexandra
A
Thanopoulou
Eleni
E
Angelopoulou
Maria K
MK
Vassilakopoulos
Theodoros P
TP
Pangalis
Gerassimos A
GA
Zoumbos
Nicholas C
NC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000209:etiology* / Q000503:physiopathology; D001853:Bone Marrow / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000473:pathology; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000473:pathology; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000097:blood; D005260:Female; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D017254:Leukemic Infiltration; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016298:Hematopoietic Cell Growth Factors; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin