title: Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation.
abstract: Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and young preleukemic animals, carried out microarray and methylation profiling analyses, and compared the results from the two groups of animals. Surprisingly, in the absence of secondary lesions, PML/RARA had an overall limited impact on both the transcriptome and methylome. Of interest, we did identify down-regulation of secondary and tertiary granule genes as the first step engaging the myeloid maturation block. Although initially not sufficient to arrest terminal granulopoiesis in vivo, such alterations set the stage for the later, complete differentiation block seen in leukemia. Further, gene set enrichment analysis revealed that PML/RARA promyelocytes exhibit a subtle increase in expression of cell cycle genes, and we show that this leads to both increased proliferation of these cells and expansion of the promyelocyte compartment. Importantly, this proliferation signature was absent from the poorly leukemogenic p50/RARA fusion model, implying a critical role for PML in the altered cell-cycle kinetics and ability to initiate leukemia. Thus, our findings challenge the predominant model in the field and we propose that PML/RARA initiates leukemia by subtly shifting cell fate decisions within the promyelocyte compartment.
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA, USA Institut Universitaire d'Hématologie, Université Paris-Diderot UMR 944/7212, France.
authors.forename: Coline
authors.initials: C
authors.lastname: Gaillard
authors.affiliation: Computational Biology Core, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Taku A
authors.initials: TA
authors.lastname: Tokuyasu
authors.affiliation: Center for Cancer and Blood Disorders, Phoenix Children's Hospital, AZ, USA.
authors.forename: Galit
authors.initials: G
authors.lastname: Rosen
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Sotzen
authors.affiliation: Institut Universitaire d'Hématologie, Université Paris-Diderot UMR 944/7212, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vitaliano-Prunier
authors.affiliation: Computational Biology Core, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.affiliation: Department of Medicine, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
authors.affiliation: Institut Universitaire d'Hématologie, Université Paris-Diderot UMR 944/7212, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA, USA scott.Kogan@ucsf.edu.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D019175:DNA Methylation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D042381:Granulocyte Precursor Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D018952:Antigens, CD34; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein