title: Modeling acute promyelocytic leukemia in the mouse: new insights in the pathogenesis of human leukemias.
abstract: Acute promyelocytic leukemia (APL) is characterized by the expansion of malignant myeloid cells blocked at the promyelocytic stage of differentiation and is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17. As a consequence of the translocation, RARalpha variably fuses to the PML, PLZF, NPM, NuMA, and Stat5b genes (X genes), respectively, leading to the generation of RARalpha-X and X-RARalpha fusion genes. The aberrant chimeric proteins encoded by these genes, as well as the inactivation of the X and RARalpha functions, may exert a crucial role in leukemogenesis. To define the molecular genetics of APL and the contribution of each molecular event in APL pathogenesis, we have generated transgenic mice harboring X-RARalpha and/or RARalpha-X genes as well as mice where the various X genes have been inactivated by homologous recombination. Here we show that while the X-RARalpha fusion gene is crucial for leukemogenesis, the presence of RARalpha-X and the inactivation of X function are critical in modulating the onset as well as the phenotype of the leukemia.
authors.affiliation: Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: T
authors.initials: T
authors.lastname: Merghoub
authors.forename: C
authors.initials: C
authors.lastname: Gurrieri
authors.forename: F
authors.initials: F
authors.lastname: Piazza
authors.forename: P P
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics
chemical_list: D015514:Oncogene Proteins, Fusion