All-trans retinoic acid rapidly decreases cathepsin G synthesis and mRNA expression in acute promyelocytic leukemia

The cells from patients with acute promyelocytic leukemia (AML M3) undergo terminal differentiation when treated with all-trans retinoic acid (ATRA). We have analyzed the expression of the mRNA for cathepsin G, a promyelocyte stage-specific transcript, in the leukemia and in retinoic acid responsive cell lines. We showed that the transcript is perpetually synthesized in patients' cells and that it rapidly disappears when the cells are treated with ATRA. In ATRA-sensitive (HL-60, NB4) cell lines and an ATRA-resistant (HL-60R) cell line we have shown that this process is dependent on proteins synthesized during the first 6h of ATRA-triggered differentiation and may involve both pre- and post-transcriptional mechanisms. A corresponding decrease in cathepsin G protein synthesis then follows. These findings indicate that the maturation arrest in AML M3 results in cells that may constitutively continue to produce proteins whose production is temporally confined during normal hemopoiesis. This would explain the elevated plasma-free serine protease activity we have demonstrated in this disease, and has implications for both the coagulopathy and the 'retinoic acid syndrome' in AML M3.