title: PML-RARA can increase hematopoietic  self-renewal without causing a  myeloproliferative disease in mice.
abstract: Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation that generates the fusion protein promyelocytic leukemia-retinoic acid receptor α (PML-RARA) in nearly all cases. Multiple prior mouse models of APL constitutively express PML-RARA from a variety of non-Pml loci. Typically, all animals develop a myeloproliferative disease, followed by leukemia in a subset of animals after a long latent period. In contrast, human APL is not associated with an antecedent stage of myeloproliferation. To address this discrepancy, we have generated a system whereby PML-RARA expression is somatically acquired from the mouse Pml locus in the context of Pml haploinsufficiency. We found that physiologic PML-RARA expression was sufficient to direct a hematopoietic progenitor self-renewal program in vitro and in vivo. However, this expansion was not associated with evidence of myeloproliferation, more accurately reflecting the clinical presentation of human APL. Thus, at physiologic doses, PML-RARA primarily acts to increase hematopoietic progenitor self-renewal, expanding a population of cells that are susceptible to acquiring secondary mutations that cause progression to leukemia. This mouse model provides a platform for more accurately dissecting the early events in APL pathogenesis.
authors.affiliation: Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63119, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Welch
authors.forename: Wenlin
authors.initials: W
authors.lastname: Yuan
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D005260:Female; D015870:Gene Expression; D006410:Hematopoiesis / Q000235:genetics* / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
chemical_list: D017931:DNA Primers; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein