MODULATION OF HUMAN G-CSF RECEPTOR MESSENGER-RNA AND PROTEIN IN NORMAL AND LEUKEMIC MYELOID CELLS BY G-CSF AND RETINOIC ACID

Granulocyte colony-stimulating factor (G-CSF) is produced by several cell types throughout the body and has a variety of effects on neutrophils and their precursors, which are mediated by binding to its receptor, It is not yet known what physiologic factors modulate G-CSF receptor mRNA expression in these cells, We studied the effect of G-CSF on freshly isolated neutrophils and bone marrow cells from normal human subjects and on myeloid leukemic cell lines, We found that G-CSF receptor mRNA levels were maintained by G-CSF in neutrophils but not in bone marrow cells, Of the leukemic cell lines tested, K562 and BV173, both of which contain the bcr-abl translocation, neither expressed G-CSF receptor mRNA, Whereas C-CSF did not affect mRNA levels for its receptor in myeloid leukemic cell lines, exposure of the acute promyelocytic cell line, NB4, to all-trans retinoic acid induced a striking increase in G-CSF receptor mRNA expression and resulted in increased G-CSF receptor surface expression, The effect of retinoic acid on G-CSF receptor mRNA on NB4 cells occurred early, before morphologic evidence of differentiation, and required protein synthesis, All-trans retinoic acid also upregulated G-CSF receptor mRNA in the myeloid leukemia cell line HL-60. Thus, maintenance of G-CSF receptor on neutrophils by G-CSF may extend the duration of ligand responsiveness, Furthermore, the ability of retinoic acid to up-regulate G-CSF receptor may account for the synergistic effect of G-CSF and retinoic acid in differentiation induction of acute promyelocytic leukemia.