title: The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model.
abstract: A t(2;5) (p23;q35) chromosomal translocation can be found in a high percentage of anaplastic large-cell lymphomas (ALCL). This genetic abnormality leads to the expression of the NPM-ALK fusion protein, which encodes a constitutively active tyrosine kinase that plays a causative role in lymphomagenesis. Employing a modified infection/transplantation protocol utilizing an MSCV-based vector, we were able to reproducibly induce two phenotypically different lymphoma-like diseases dependent on the retroviral titers used. The first phenotype presented as a polyclonal histiocytic malignancy of myeloid/macrophage origin with a short latency period of 3-4 weeks. Clinically, the diseased mice showed rapidly progressive wasting, lymphadenopathy and pancytopenia. Mice displaying the second phenotype developed monoclonal B-lymphoid tumors with a longer latency of approximately 12-16 weeks, primarily involving the spleen and the bone marrow, with less extensive lymph node but also histologically evident extranodal organ infiltration by large immature plasmoblastic cells. The described retroviral mouse model will be useful to analyse the role of NPM-ALK in lymphomagenesis in vivo and may contribute to the development of new treatment options for NPM-ALK induced malignancies.
authors.affiliation: Department of Internal Medicine III, Technical University of Munich, Trogerstr. 32, D-81675 Munich, Germany.
authors.forename: Cornelius
authors.initials: C
authors.lastname: Miething
authors.forename: Rebekka
authors.initials: R
authors.lastname: Grundler
authors.forename: Falco
authors.initials: F
authors.lastname: Fend
authors.forename: Josef
authors.initials: J
authors.lastname: Hoepfl
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugler
authors.forename: Christoph
authors.initials: C
authors.lastname: von Schilling
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
mesh_terms: D000818:Animals; D002469:Cell Separation; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics*; D013997:Time Factors
chemical_list: D018076:DNA, Complementary; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases