title: Hematopoietic neoplasms in Prkar2a-deficient mice.
abstract: BACKGROUND
  Protein kinase A (PKA) is a holoenzyme that consists of a dimer of regulatory subunits and two inactive catalytic subunits that bind to the regulatory subunit dimer. Four regulatory subunits (RIα, RIβ, RIIα, RIIβ) and four catalytic subunits (Cα, Cβ, Cγ, Prkx) have been described in the human and mouse genomes. Previous studies showed that complete inactivation of the Prkar1a subunit (coding for RIα) in the germline leads to embryonic lethality, while Prkar1a-deficient mice are viable and develop schwannomas, thyroid, and bone neoplasms, and rarely lymphomas and sarcomas. Mice with inactivation of the Prkar2a and Prkar2b genes (coding for RIIα and RIIβ, respectively) are also viable but have not been studied for their susceptibility to any tumors.
  
  
  METHODS
  Cohorts of Prkar1a (+/-) , Prkar2a (+/-) , Prkar2a (-/-) , Prkar2b (+/-) and wild type (WT) mice have been observed between 5 and 25 months of age for the development of hematologic malignancies. Tissues were studied by immunohistochemistry; tumor-specific markers were also used as indicated. Cell sorting and protein studies were also performed.
  
  
  RESULTS
  Both Prkar2a (-/-) and Prkar2a (+/-) mice frequently developed hematopoietic neoplasms dominated by histiocytic sarcomas (HS) with rare diffuse large B cell lymphomas (DLBCL). Southern blot analysis confirmed that the tumors diagnosed histologically as DLBCL were clonal B cell neoplasms. Mice with other genotypes did not develop a significant number of similar neoplasms.
  
  
  CONCLUSIONS
  Prkar2a deficiency predisposes to hematopoietic malignancies in vivo. RIIα's likely association with HS and DLBCL was hitherto unrecognized and may lead to better understanding of these rare neoplasms.
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA. esaloustros@yahoo.gr.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Saloustros
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA. salpeapa@mail.nih.gov.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Salpea
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5640 Fishers Lane, Rockville, MD, 20852, USA. cqi@niaid.nih.gov.
authors.forename: Chen-Feng
authors.initials: CF
authors.lastname: Qi
authors.affiliation: Program in Genomics and Differentiation, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA. laguglio@gmail.com.
authors.forename: Lina A
authors.initials: LA
authors.lastname: Gugliotti
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA. kitman1214@gmail.com.
authors.forename: Kitman
authors.initials: K
authors.lastname: Tsang
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA. sisi.liu@nih.gov.
authors.forename: Sisi
authors.initials: S
authors.lastname: Liu
authors.affiliation: Division of Veterinary Resources, Office of the Director (OD), National Institutes of Health, Bethesda, MD, 20892, USA. starostm@ors.od.nih.gov.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5640 Fishers Lane, Rockville, MD, 20852, USA. hmorse@niaid.nih.gov.
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.affiliation: Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) & Pediatric Endocrinology Inter-institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA. stratakc@mail.nih.gov.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000473:pathology; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D013997:Time Factors
chemical_list: D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit