Abstract 3854: Novel hematopoietic neoplasms in prkar2a- deficient mice.

Abstract

Abstract Background: Histiocytic sarcoma (HS) is an aggressive hematological neoplasm that responds poorly to therapy. The molecular etiology and pathology of this disease remain unclear, hampering the development of an effective therapy. Therefore, a need for more, and more realistic, animal models remains. Lymphoproliferative disorders have been reported in mice deficient for the prkar1a gene coding for the regulatory subunit type 1A of protein kinase A (PKA), but nothing is known about the role of type II PKA regulatory subunits in hematologic malignancies. Methods: Mice deficient for the Prkar1a and Prkar2a alleles were previously reported (Kirschner et al, 2005 και Burton et al, 1997) and were kept on a mixed genetic background (C57BL/129Sv). Mice were crossed to create prkar2a+/- and prkar2a-/-. Mice were phenotyped at the ages of 3-6-9-12-18 months or when they exhibited signs of advanced disease. Tissues were collected for histological and molecular analysis. Results: Unexpectedly, mice deficient for the prkar2a allele(s) developed lymphomas, with significant higher incidence compared to the prkar1a+/- mice [8/13 (61.5%) of the prkar2a+/- and 5/8 (62.5%) of the prkar2a-/- vs. 3/21(14.2%) of the prkar1a+/-, Fisher's exact test p=0.02]. Histology studies of sections stained with H&E revealed a variety of pathologic changes in lymphoid and non-lymphoid tissues. Lesions characteristic of histiocytic sarcoma (HS) were found in spleen and abdominal lymph nodes, sometimes associated with leukemic infiltrates in lung and bone marrow (BM). Abnormal megakaryopoiesis in spleen and BM was associated with cells actively phagocytosing red cells, others with a pseudo Gaucher-like appearance and increased immature forms. Erythropoiesis was reduced in BM and spleen. Vascular thrombi were associated with schistocytosis. Accumulations of mostly mature plasma cells and some plasmablasts were present in the splenic red pulp together with large, active germinal centers. Cells with characteristics of diffuse large B cell lymphoma often occupied expanded splenic follicles and lymph nodes. Kidneys exhibited degenerative changes in glomeruli and tubules. Median age at presentation was 18 months (range 16-25 months). FACS analysis of BM cells revealed a decrease in late pro-B cells in the prkar2a deficient mice compared to the wild-type, indicating a developmental block at this stage of early B cell differentiation. Interestingly, Southern blot analysis of these B cell lymphomas showed that in most cases they were monoclonal with either one or both IgH alleles rearranged. Conclusions: Our data indicate that PRKAR2a may be involved in the development of malignant lesions of the hematologic lineage. The presented mouse model can be used to gain insights into the molecular and cellular origins of this rare neoplasm and provide a preclinical model in which to test novel therapeutic strategies. Citation Format: Emmanouil Saloustros, Paraskevi Salpea, Lina Gugglioti, Kittman Tsang, Anelia Horvath, Maria Nesterova, Chen-Feng Qi, Herbert C. Morse III, Constantine A. Stratakis. Novel hematopoietic neoplasms in prkar2a- deficient mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3854. doi:10.1158/1538-7445.AM2013-3854