Two distinctly regulated events, priming and triggering, during retinoid-induced maturation and resistance of NB4 promyelocytic leukemia cell line.

Abstract

In t(15;17) acute promyelocytic leukema, all-trans retinoic acid (RA) induces leukemic cell maturation in vitro and remission in acute promyelocytic leukemia patients, but in vivo treatments invariably lead to relapse with resistance to RA. NB4, a maturation-inducible cell line, and NB4-RAr sublines (Ri and R2) displaying no maturation in the presence of RA have been isolated from a patient in relapse. We show that resistance to maturation is not a mere unresponsiveness to RA: rather, R1

Retinoic acid resistance in NB4 APL cells is associated with lack of interferon α synthesis Stat1 and p48 induction

“…RA and cAMP which show synergistic activity in inducing maturation of NB4 cells and maturation of the RA`primed' NB4-R1 resistant cells (Ruchaud et al, 1994), distinctly modulate Stat1, p48 and IRF-1 expressions (this paper). In NB4 cells, RA and cAMP act synergistically to induce IFN synthesis and the expression of Stat1, IRF-1 and p48.…”

“…The NB4 APL and the NB4-derived cell lines (NB4-R1 and NB4-R2) were kindly provided by M Lanotte (Duprez et al, 1992;Lanotte et al, 1991;Ruchaud et al, 1994). These cell lines were grown in RPMI-1640 supplemented with 10% FCS under the same conditions as previously reported for the isolation and maintenance of the NB4 cell line.…”

“…Two distinct types of maturation de®cient NB4 cell sublines, NB4-R1 and NB4-R2, were isolated from the RA-sensitive parental line (Ruchaud et al, 1994). It has been shown that the basal level of RARa, RXRa and PML mRNAs and proteins were roughly the same in the three cell lines (Duprez et al, 1996a).…”

The transcriptional repressor ICER and cAMP-induced programmed cell death

“…Indeed, cAMP induces apoptosis in thymocytes McConkey et al, 1992;Susuki et al, 1990), while it stimulates proliferation of epithelial cells and neuronal cell di erentiation (Freidman, 1976;Dumont et al, 1989). Importantly, cAMP synergises with glucocorticoids and PKC signalling in inducing apoptosis (McConkey et al, 1990;Susuki et al, 1990;Groul and Altschmeid, 1993;reviewed in McConkey et al, 1992), while it cooperates with retinoids in the di erentiation of teratocarcinoma cells (Hu and Gudas, 1990;WeilerGuetter et al, 1992) and of various leukaemia cells (Olsson et al, 1982;Gianni et al, 1995;Ruchaud et al, 1994).…”

“…cAMP induces monocytic di erentiation of M1 mouse myeloid leukaemia (Homma et al, 1978) and of a subclone of HL60 cells (Tortora et al, 1988). It potentiates granulocytic di erentiation of retinoidinduced maturation of human myeloid leukaemia cells (Olsson et al, 1982;Ruchaud et al, 1994). cAMP signalling triggers apoptosis in normal and leukaemic thymocytes and in myeloid leukaemia cells.…”