title: Transgenic expression of PML/RARalpha impairs myelopoiesis.
abstract: The translocation found in acute promyelocytic leukemia rearranges the promyelocytic leukemia gene (PML) on chromosome 15 with the retinoic acid receptor alpha (RARalpha) on chromosome 17. This yields a fusion transcript, PML/RARalpha, a transcription factor with reported dominant negative functions in the absence of hormone. Clinical remissions induced with all-trans retinoic acid (RA) treatment in acute promyelocytic leukemia are linked to PML/RARalpha expression in leukemic cells. To evaluate the PML/RARalpha role in myelopoiesis, transgenic mice expressing PML/RARalpha were engineered. A full-length PML/RARalpha cDNA driven by the CD11b promoter was expressed in transgenic mice. Expression was confirmed in the bone marrow with a reverse transcription PCR assay. Basal total white blood cell and granulocyte counts did not appreciably differ between PML/RARalpha transgenic and control mice. Cell sorter analysis of CD11b+ bone marrow cells revealed similar CD11b+ populations in transgenic and control mice. However, in vitro clonal growth assays performed on peripheral blood from transgenic versus control mice revealed a marked reduction of myeloid progenitors, especially in those responding to granulocyte/ macrophage colony-stimulating factor. Granulocyte/macrophage colony-stimulating factor and kit ligand cotreatment did not overcome this inhibition. Impaired myelopoiesis in vivo was shown by stressing these mice with sublethal irradiation. Following irradiation, PML/RARalpha transgenic mice, as compared with controls, more rapidly depressed peripheral white blood cell and granulocyte counts. As expected, nearly all control mice (94.4%) survived irradiation, yet this irradiation was lethal to 45.8% of PML/RARalpha transgenic mice. Lethality was associated with more severe leukopenia in transgenic versus control mice. Retinoic acid treatment of irradiated PML/RARalpha mice enhanced granulocyte recovery. These data suggest that abnormal myelopoiesis due to PML/RARalpha expression is an early event in oncogenic transformation.
authors: Department of Medicine, Laboratory of Molecular Medicine, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors: E
authors: E
authors: Early
authors: M A
authors: MA
authors: Moore
authors: A
authors: A
authors: Kakizuka
authors: K
authors: K
authors: Nason-Burchenal
authors: P
authors: P
authors: Martin
authors: R M
authors: RM
authors: Evans
authors: E
authors: E
authors: Dmitrovsky
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D016207:Cytokines / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D007958:Leukocyte Count / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D019089:Stem Cell Factor / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
chemical_list: D016207:Cytokines; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D012333:RNA, Messenger; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D019089:Stem Cell Factor; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D014212:Tretinoin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor