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

In the t(15;17) acute promyelocytic leukaemia (APL), all trans-retinoic (RA) treatment induces maturation leading to clinically complete but not durable remission, as RA resistance develops in the treated patients as well as in vitro. RA and interferons (IFNs) are known inhibitors of proliferation in various cells including those from APL. In this report, we show that they can act cooperatively to inhibit growth and to induce differentiation of NB4 cells but not of two RA-resistant NB4 derived cell lines, NB4-R1 and NB4-R2. However, the resistant cell lines respond to IFN. In NB4 cells, RA increases the expression of Stat1, p48 and IRF-1, three transcription factors playing a central role in the IFN response and induces the synthesis and the secretion of IFN alpha. RA-induced IFN alpha seems to play a role in inhibition of NB4 cell growth but not in their differentiation. In the resistant cells, NB4-R1 and NB4-R2, both the induction of IFN and the increase of Statl and p48 expression by RA are completely blocked. In contrast, IRF-1 mRNA and protein expressions are induced in the three cell lines. This suggests that increase of IRF-1 expression is not sufficient for IFN induction. Our results identify some defects linked to RA-resistance in APL and support the hypothesis that RA-induced Stat1 expression and IFN secretion may be one of the mechanisms mediating growth inhibition by RA.