TGF-beta inhibits growth and induces apoptosis in leukemic B cell precursors.
The uncontrolled proliferation of malignant lymphoblasts is the pathobiological hallmark in B cell precursor-ALL (BCP-ALL). Identification of inhibitory growth factors is of great importance for the understanding of growth control of leukemic B cell precursors and the development of novel therapeutic approaches in BCP-ALL. The aim of our study was the analysis of the effect of TGF-beta on cell survival and apoptosis of B cell precursors (BCP) from patients with acute lymphoblastic leukemia in vitro. Experiments were performed in a coculture system with cloned murine fibroblasts, which efficiently block spontaneous ex vivo apoptosis of BCP and thus allows the assessment of cytokine-induced growth inhibition. TGF-beta significantly reduced cell viability of highly purified, FACS isolated CD10+/CD19+ leukemic BCP by a mean of 53% (P = 0.0001). The loss of cell viability was accompanied by a significant increase of apoptosis with a mean of 70% (P = 0.0028). The TGF-beta effect was blocked specifically by a monoclonal anti-TGF-beta antibody. Induction of apoptotic cell death by TGF-beta was not accompanied by reduction of bcl-2 protein expression. TGF-beta transcription was not detected in the leukemic pre-B cell line BLIN-1, but in the murine fibroblasts. The growth inhibitory effect of TGF-beta was not restricted to leukemic BCP. The cytokine also increased apoptosis of normal, highly purified BCP by a mean of 58%. The data identify TGF-beta as a potent growth inhibitory cytokine for leukemic BCP.
Buske
C
C
Department of Hematology/Oncology, University of Göttingen, Germany.
Becker
D
D
Feuring-Buske
M
M
Hannig
H
H
Wulf
G
G
Schäfer
C
C
Hiddemann
W
W
Wörmann
B
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta