A study of growth mechanism of leukemic blast progenitors in AML.

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The growth of leukemic blast progenitors from AML patients is under the control of complex network of cytokines. Among cytokines produced by AML blasts and stimulate the growth of their own progenitors, TNF-a possess most powerful effect. We investigated the effects of various cytokines on the growth of leukemic blast progenitors and expression of proto-oncogenes, induction of apoptosis, and cell cycle of blasts.1. Role of TGF-b1. TGF-b1 did not affect the growth of G-CSF supported normal hematopoietic progenitors, but suppressed the one supported by GM-CSF, IL-3, or SCF, and the suppression by TGF-b1 was increased in this order. TGF-b1 profoundly suppressed the growth of leukemic blast progenitors, irrespective of growth factor used. By experiments with c-Myc and c-Myb antisense oligonucleotides and Northern blot analysis, c-Myc and c-Myb may be directly related to TGF-b1 suppression. In normal hematopoietic progenitors, TGF-b1 preferentially suppressed the primitive ones. In hematolo … More gic malignancies, TGF-b1 suppression was increased with progression of clonal evolution, and may be related to the activation of endogenous tyrosine kinase activity. TGF-b1 inhibited the expression of c-kit and Fas mRNA by AML blasts, and seems to act against apoptosis and differentiation.2. Role of TNF-a. TNF-a alone enhanced the transition of AML blasts to S phase, but failed to stimulate the growth of leukemic blast progenitors. In the presence of cytokine such as IL-3, TNF-a powerfully stimulated the clonogenic cell growth. TNF-a stimulated the expression of c-kit, c-jun, and Fas mRNA by blasts, and induced differentiation of the cells. TGF-b1 almost completely abolished growth stimulating effect of TNF-a.Induction of apoptosis of AML blasts. When AMl blasts were cultured in vitro in the absence of growth factor, expression of c-jun and c-fos mRNA, transition into S phase, and induction of apoptosis of the cells were observed. Addition of factor such as IL-3 prevented apoptosis and suppressed c-jun transcript and enhanced c-fos transcript. In some AML cases, cells remained in G0/G1 phase, and did not express c-jun and c-fos mRNA, and apoptosis was not observed. The proportion of c-Jun/c-Fos may play an importent role in induction of apoptosis of AML blasts. Less