Functional interactions between Lmo2, the Arf tumor suppressor, and Notch1 in murine T-cell malignancies.

Treanor LM, Volanakis EJ, Zhou S, Lu T, Sherr CJ, Sorrentino BP
Blood. 2011 117 (20): 5453-62

PMID: 21427293 · PMCID: PMC3109717 · DOI:10.1182/blood-2010-09-309831

LMO2 is a target of chromosomal translocations in T-cell tumors and was activated by retroviral vector insertions in T-cell tumors from X-SCID patients in gene therapy trials. To better understand the cooperating genetic events in LMO2-associated T-cell acute lymphoblastic leukemia (T-ALL), we investigated the roles of Arf tumor suppressor loss and Notch activation in murine models of transplantation. Lmo2 overexpression enhanced the expansion of primitive DN2 thymocytes, eventually facilitating the stochastic induction of clonal CD4(+)/CD8(+) malignancies. Inactivation of the Arf tumor suppressor further increased the self-renewal capacity of the primitive, preleukemic thymocyte pool and accelerated the development of aggressive, Lmo2-induced T-cell lympholeukemias. Notch mutations were frequently detected in these Lmo2-induced tumors. The Arf promoter was not directly engaged by Lmo2 or mutant Notch, and use of a mouse model in which activation of a mutant Notch allele depends on previous engagement of the Arf promoter revealed that Notch activation could occur as a subsequent event in T-cell tumorigenesis. Therefore, Lmo2 cooperates with Arf loss to enhance self-renewal in primitive thymocytes. Notch mutation and Arf inactivation appear to independently cooperate in no requisite order with Lmo2 overexpression in inducing T-ALL, and all 3 events remained insufficient to guarantee immediate tumor development.

MeSH Terms (24)

Adaptor Proteins, Signal Transducing Animals Cell Transformation, Neoplastic Cocarcinogenesis Cyclin-Dependent Kinase Inhibitor p16 Disease Progression DNA-Binding Proteins Female Gene Expression LIM Domain Proteins Loss of Heterozygosity Male Metalloproteins Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mutation Neoplastic Stem Cells Precursor Cells, T-Lymphoid Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Promoter Regions, Genetic Receptor, Notch1 Signal Transduction

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