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MOHITO, a novel mouse cytokine-dependent T-cell line, enables studies of oncogenic signaling in the T-cell context.

ABSTRACT: The mouse pro-B cell line Ba/F3 has gained major interest as a model system to investigate oncogenic tyrosine kinases and to determine the efficacy of kinase inhibitors. While Ba/F3 cells are suitable to study oncogenic kinases derived from various cell types, the signaling networks in Ba/F3 cells are B-cell specific. We have established a mouse CD4+CD8+ double positive T-cell line (named MOHITO, for MOuse Hematopoietic Interleukin-dependent cell line of T-cell Origin) that has many features of human T-cell acute lymphoblastic leukemia (Notch1 and Jak1 mutation, TCR rearrangement) and is dependent on interleukin-7. The MOHITO cell line can be transformed to cytokine independent proliferation by BCR-ABL1 or mutant JAK1. This mouse T-cell line is a novel model system to investigate protein signaling and inhibition in a T-cell specific context and is a valuable tool to study and verify oncogenic capacity of mutations in the kinome and phosphatome in T-cell malignancies.

SUBMITTER: Kleppe M

PROVIDER: S-EPMC3084928 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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MOHITO, a novel mouse cytokine-dependent T-cell line, enables studies of oncogenic signaling in the T-cell context.

Kleppe Maria M Mentens Nicole N Tousseyn Thomas T Wlodarska Iwona I Cools Jan J

Haematologica 20101229 5

The mouse pro-B cell line Ba/F3 has gained major interest as a model system to investigate oncogenic tyrosine kinases and to determine the efficacy of kinase inhibitors. While Ba/F3 cells are suitable to study oncogenic kinases derived from various cell types, the signaling networks in Ba/F3 cells are B-cell specific. We have established a mouse CD4+CD8+ double positive T-cell line (named MOHITO, for MOuse Hematopoietic Interleukin-dependent cell line of T-cell Origin) that has many features of ...[more]

PMID: 21193420

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Project description:Ifitm3 (interferon-inducible transmembrane protein 3) was previously identified as an endosomal antiviral effector protein that blocks viral infection1-4. In analyses of gene expression data from patients with B-cell leukemia and lymphoma, we identified Ifitm3 as one of the strongest predictors of poor clinical outcome. In normal resting B-cells, Ifitm3 was minimally expressed and mainly localized in endosomes. However, engagement of the B-cell receptor (BCR) and PI3K-activation strongly induced expression of Ifitm3 and phosphorylation of its N-terminus at Y20, resulting in accumulation at the cell surface. In B-cell leukemia, oncogenic kinases induced phosphorylation at Y20, resulting in constitutive plasma membrane localization of Ifitm3. Ifitm3¯ / ¯ naïve B-cells developed at normal numbers, however, B-cell activation upon antigen encounter, germinal center formation and production of antigen-specific antibodies were compromised. Likewise, oncogenes that typically induce development of leukemia and lymphoma failed to transform Ifitm3¯ / ¯ B-cells. Conversely, a phosphomimetic mutation of Y20 induced oncogenic PI3K-signaling and initiated transformation of premalignant B-cells into overt leukemia. Functional experiments revealed a previously unrecognized function of Ifitm3 as PIP3-scaffold and central amplifier of PI3K signaling downstream of the BCR and adhesion receptors. PI3K signal-amplification depends on binding of Ifitm3 to PIP3 via two lysine residues (K83 and K104) in its conserved intracellular loop. In Ifitm3¯ / ¯ B-cells, lipid rafts were depleted of PIP3, resulting in defective expression of >60 lipid raft-associated surface receptors, which impaired BCR-signaling and cellular adhesion. We conclude that phosphorylation of IFITM3 upon Bcell antigen-encounter induces a dynamic switch from antiviral effector functions in endosomes to a PI3K-amplification loop at the cell surface. IFITM3-dependent amplification of PI3K-signaling downstream of the BCR and adhesion receptors is critical to enable rapid expansion of B-cells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3- dependent signaling complexes and amplify PI3K-signaling for malignant transformation.

Dataset Information

MOHITO, a novel mouse cytokine-dependent T-cell line, enables studies of oncogenic signaling in the T-cell context.

Publications

MOHITO, a novel mouse cytokine-dependent T-cell line, enables studies of oncogenic signaling in the T-cell context.

Similar Datasets

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