Unexpected features of acute T lymphoblastic lymphomas in Notch1IC transgenic rats.
Dysregulated Notch signaling accounts for the majority of acute T lymphoblastic leukemia/lymphoma (T-ALL) cases in humans. Here, we characterize lymphomas from Notch1IC transgenic rats, which develop T-ALL shortly after weaning, and show that they display a number of previously undocumented features. Starting from monoclonal thymic tumors, the CD4(+)CD8alphaalpha(+) lymphoma cells infiltrate the bone marrow and then spread to secondary lymphoid and non-lymphoid organs. However, major hallmarks of T-ALL cells in other murine models and human patients, such as constitutive NF-kappaB activity and increased levels of anti-apoptotic proteins, are remarkably absent in Notch1IC lymphomas. In contrast, CD30, a classic marker of Hodgkin lymphomas, is overexpressed in these tumors. Intriguingly, enforced Notch1 signaling up-regulates expression of Notch3, which has also been implicated in the pathogenesis of T-ALL. By blocking endogenous Notch signaling, we could demonstrate that Notch1IC is sufficient to induce sustained preTCR expression in transgenic thymocytes but not for their progression to the double-positive stage. This suggests that other Notch activities may also contribute to the phenotype of the transgenic rats. In summary, we anticipate this new animal model will help to further elucidate the role of Notch1 in the pathogenesis of T-ALL.
van den Brandt
Jens
J
Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
Kwon
Soon-Hwan
SH
McPherson
Kirsty G
KG
Petrovic
Suzana
S
Zettl
Andreas
A
Müller-Hermelink
Hans Konrad
HK
Reichardt
Holger M
HM
D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017730:Ki-1 Antigen / Q000235:genetics / Q000378:metabolism; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D000071656:Receptor, Notch3; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D017730:Ki-1 Antigen; D016328:NF-kappa B; C497763:Notch1 protein, rat; C498556:Notch3 protein, rat; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch