The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model.
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.
Miething
Cornelius
C
Department of Internal Medicine III, Technical University of Munich, Trogerstr. 32, D-81675 Munich, Germany.
Grundler
Rebekka
R
Fend
Falco
F
Hoepfl
Josef
J
Mugler
Claudia
C
von Schilling
Christoph
C
Morris
Stephan W
SW
Peschel
Christian
C
Duyster
Justus
J
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
D018076:DNA, Complementary; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases