ALTERED MYELOID DEVELOPMENT AND ACUTE-LEUKEMIA IN TRANSGENIC MICE EXPRESSING PML-RAR-ALPHA UNDER CONTROL OF CATHEPSIN-G REGULATORY SEQUENCES

Acute promyelocytic leukemia (APML) is characterized by abnormal myelo id development, resulting an accumulation of leukemic promyelocytes th at are often highly sensitive to retinoic acid. A balanced t(15;17) (q 22;q21) reciprocal chromosomal translocation is found in approximately 90% of APML patients; this translocation fuses the PML gene on chromo some 15 to the retinoic acid receptor alpha (RAR alpha) gene on chromo some 17, creating two novel fusion genes, PML-RAR alpha and RAR alpha- PML. The PML-RAR alpha fusion gene product, which is expressed in virt ually all patients with t(15;17), is thought to play a direct role in the pathogenesis of APML. To determine whether PML-RAR alpha is suffic ient to cause APML in an animal model, we used the promyelocyte-specif ic targeting sequences of the human cathepsin G (hCG) gene to direct t he expression of a PML-RAR alpha cDNA to the early myeloid cells of tr ansgenic mice. Mice expressing the hCG-PML-RAR alpha transgene were fo und to have altered myeloid development that was characterized by incr eased percentages of immature and mature myeloid cells in the peripher al blood, bone marrow, and spleen. In addition, approximately 30% of t ransgene-expressing mice eventually developed acute myeloid leukemia a fter a long latent period. The splenic promyelocytes of mice with both the nonleukemic and leukemic phenotypes responded to all-trans retino ic acid (ATRA) treatment, which caused apoptosis of myeloid precursors . Although low-level expression of the hCG-PML-RAR alpha transgene is not sufficient to directly cause acute myeloid leukemia in mice, its e xpression alters myeloid development, resulting in an accumulation of myeloid precursors that may be susceptible to cooperative transforming events. (C) 1997 by The American Society of Hematology.