Altered myeloid development and acute leukemia in transgenic mice expressing PML-RARα under control of cathepsin G regulatory sequences

JL Grisolano, RL Wesselschmidt… - Blood, The Journal of …, 1997 - ashpublications.org
JL Grisolano, RL Wesselschmidt, PG Pelicci, TJ Ley
Blood, The Journal of the American Society of Hematology, 1997ashpublications.org
Acute promyelocytic leukemia (APML) is characterized by abnormal myeloid development,
resulting an accumulation of leukemic promyelocytes that are often highly sensitive to
retinoic acid. A balanced t (15; 17)(q22; q21) reciprocal chromosomal translocation is found
in approximately 90% of APML patients; this translocation fuses the PML gene on
chromosome 15 to the retinoic acid receptor α (RARα) gene on chromosome 17, creating
two novel fusion genes, PML-RARα and RARα-PML. The PML-RARα fusion gene product …
Abstract
Acute promyelocytic leukemia (APML) is characterized by abnormal myeloid development, resulting an accumulation of leukemic promyelocytes that are often highly sensitive to retinoic acid. A balanced t(15; 17) (q22; q21) reciprocal chromosomal translocation is found in approximately 90% of APML patients; this translocation fuses the PML gene on chromosome 15 to the retinoic acid receptor α (RARα) gene on chromosome 17, creating two novel fusion genes, PML-RARα and RARα-PML. The PML-RARα fusion gene product, which is expressed in virtually all patients with t(15; 17), is thought to play a direct role in the pathogenesis of APML. To determine whether PML-RARα is sufficient to cause APML in an animal model, we used the promyelocyte-specific targeting sequences of the human cathepsin G (hCG) gene to direct the expression of a PML-RARα cDNA to the early myeloid cells of transgenic mice. Mice expressing the hCG–PML-RARα transgene were found to have altered myeloid development that was characterized by increased percentages of immature and mature myeloid cells in the peripheral blood, bone marrow, and spleen. In addition, approximately 30% of transgene-expressing mice eventually developed acute myeloid leukemia after a long latent period. The splenic promyelocytes of mice with both the nonleukemic and leukemic phenotypes responded to all-trans retinoic acid (ATRA) treatment, which caused apoptosis of myeloid precursors. Although low-level expression of the hCG–PML-RARα transgene is not sufficient to directly cause acute myeloid leukemia in mice, its expression alters myeloid development, resulting in an accumulation of myeloid precursors that may be susceptible to cooperative transforming events.
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