Tumor necrosis factor alpha down-regulates c-myc mRNA expression and induces in vitro monocytic differentiation in fresh blast cells from patients with acute myeloblastic leukemia.
We have studied tumor necrosis factor alpha (TNF-alpha) for its capacity to induce differentiation and to modulate c-myc and c-fms protooncogene mRNA expression in fresh blasts from 10 patients with acute myeloblastic leukemia (AML). Bone marrow blast cells were grown in suspension cultures in the presence of 500 U/ml (62 ng/ml) of TNF-alpha for 7 days. Induction of differentiation was assessed by means of morphology, cytochemistry, immunophenotyping (CD11b, CD13, CD14, CD33), and nitroblue tetrazolium reduction. In all cases, exposure of leukemic blasts to TNF-alpha resulted in phenotypic changes consistent with induction of differentiation, although a marked variability in degree and type of response was observed. The majority of cases developed monocytic morphology and showed significant increases (chi 2 test, p less than 0.05) in phagocytic activity and/or expression of ANAE and myelomonocytic differentiation antigens (CD11b, CD14). TNF-alpha reduced c-myc mRNA level over a period of 24 hr in four of six cases studied: the two cases with no down-regulation were the least responsive in terms of myelomonocytic differentiation. These results confirm those obtained with leukemic cell lines, suggesting that TNF-alpha can induce differentiation of fresh AML blasts, mainly toward the monocytic lineage, and that induction of differentiation seems to be closely linked to down-regulation of c-myc mRNA expression over the first 24 hr rather than to attenuation of cellular proliferation per se.
Bergamaschi
G
G
Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, Italy.
Carlo-Stella
C
C
Cazzola
M
M
De Fazio
P
P
Pedrazzoli
P
P
Peverali
F A
FA
Della Valle
G
G
D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation; D016009:Chi-Square Distribution; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000473:pathology*; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha