Retinoic acid receptor (RAR)-alpha mRNA expression was studied in a variety of myeloid leukemia cells with variable responsiveness to the induction of terminal differentiation by retinoic acid (RA). Cells from both the wild-type (wt), RA-responsive HL-60 promyelocytic leukemia cell line and a selected greater than or equal to 300-fold RA-resistant subline expressed approximately equal amounts of two RAR-alpha transcripts, 4.0 and 3.1 kb in size. In wt cells, the RAR-alpha did not change during induction of granulocyte differentiation by RA or macrophagic differentiation by 12-0-tetradecanoylphorbol-13-acetate (TPA). Relative to HL-60 cells, other cultured and fresh myeloid leukemia cells expressed 2.5-fold less to equal amounts of the RAR-alpha transcripts. The relative expression in six cases of acute promyelocytic leukemia (APL; two RA-responsive; one, previously treated with 13-cis-RA in vivo, equivocally RA-responsive) and one case of acute myelogenous leukemia (AML) with promyelocytosis (RA unresponsive) was 0.91 +/- 0.14 versus 0.53 +/- 0.14 for eight cases of nonpromyelocytic AML (p congruent to 0.001). Lymphoid leukemia cells expressed 2- to 5-fold less RAR-alpha mRNA. No qualitative variations in the mRNA transcripts were observed, although the 3.1 kb transcript was relatively decreased in three cases. The RAR-alpha gene was not amplified or detectably rearranged in any DNA source, although an apparent EcoRI restriction fragment length polymorphism was observed. It is concluded (a) that the steady-state level of RAR-alpha mRNA is not tightly correlated with natural responsiveness/unresponsiveness or, in some instances, acquired resistance to RA-induced differentiation and (b) that further studies are needed to determine if the mean 1.7-fold higher RAR-alpha mRNA level in APL cells could be an essential factor in the RA-responsiveness of APL cells, as primarily regulated at a different molecular level.