Trib2 Suppresses Tumor Initiation in Notch-Driven T-ALL

• Published in: PloS one 2016-05, Vol.11 (5), p.e0155408-e0155408
• Main Authors: Stein, Sarah J, Mack, Ethan A, Rome, Kelly S, Pajcini, Kostandin V, Ohtani, Takuya, Xu, Lanwei, Li, Yunlei, Meijerink, Jules P P, Faryabi, Robert B, Pear, Warren S
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Acute lymphocytic leukemia; AKT protein; Analysis; Animals; Biology and Life Sciences; Biotechnology; Cancer; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell survival; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Clonal deletion; Cortex; Development and progression; Disease Models, Animal; Engineering; Gene Expression; Gene Targeting; Genetic aspects; Genetic Loci; Genomes; Hematology; Hematopoiesis; Immunoblotting; Immunology; In vivo methods and tests; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Laboratories; Latency; Leukemia; Leukemogenesis; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Medical research; Medicine; Medicine and Health Sciences; Mice; Mice, Knockout; Mutation; Notch protein; Pathogenesis; Pathology; Pediatrics; Penetrance; Phosphorylation; Physiological aspects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Receptors, Notch - metabolism; Research and Analysis Methods; Signal Transduction; Stem cells; Survival; Survival factor; T cells; Tlx1 protein; Transcription; Tumor suppressor genes; Tumorigenesis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0155408

Trib2 is highly expressed in human T cell acute lymphoblastic leukemia (T-ALL) and is a direct transcriptional target of the oncogenic drivers Notch and TAL1. In human TAL1-driven T-ALL cell lines, Trib2 is proposed to function as an important survival factor, but there is limited information about the role of Trib2 in primary T-ALL. In this study, we investigated the role of Trib2 in the initiation and maintenance of Notch-dependent T-ALL. Trib2 had no effect on the growth and survival of murine T-ALL cell lines in vitro when expression was blocked by shRNAs. To test the function of Trib2 on leukemogenesis in vivo, we generated Trib2 knockout mice. Mice were born at the expected Mendelian frequencies without gross developmental anomalies. Adult mice did not develop pathology or shortened survival, and hematopoiesis, including T cell development, was unperturbed. Using a retroviral model of Notch-induced T-ALL, deletion of Trib2 unexpectedly decreased the latency and increased the penetrance of T-ALL development in vivo. Immunoblotting of primary murine T-ALL cells showed that the absence of Trib2 increased C/EBPα expression, a known regulator of cell proliferation, and did not alter AKT or ERK phosphorylation. Although Trib2 was suggested to be highly expressed in T-ALL, transcriptomic analysis of two independent T-ALL cohorts showed that low Trib2 expression correlated with the TLX1-expressing cortical mature T-ALL subtype, whereas high Trib2 expression correlated with the LYL1-expressing early immature T-ALL subtype. These data indicate that Trib2 has a complex role in the pathogenesis of Notch-driven T-ALL, which may vary between different T-ALL subtypes.