title: 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.
abstract: 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.
authors.affiliation: Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Bergamaschi
authors.forename: C
authors.initials: C
authors.lastname: Carlo-Stella
authors.forename: M
authors.initials: M
authors.lastname: Cazzola
authors.forename: P
authors.initials: P
authors.lastname: De Fazio
authors.forename: P
authors.initials: P
authors.lastname: Pedrazzoli
authors.forename: F A
authors.initials: FA
authors.lastname: Peverali
authors.forename: G
authors.initials: G
authors.lastname: Della Valle
mesh_terms: 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*
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha