MNT suppresses T cell apoptosis via BIM and is critical for T lymphomagenesis

The importance of c-MYC in regulating lymphopoiesis and promoting lymphomagenesis is well-established. Far less appreciated is the vital supporting role of MYC’s relative MNT. Using Rag1Cr e-mediated Mnt deletion in lymphoid progenitor cells, we show here that, during normal T cell development, MNT...

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Bibliographic Details
Published in:Cell death and differentiation 2023-04, Vol.30 (4), p.1018-1032
Main Authors: Nguyen, Hai Vu, Vandenberg, Cassandra J., Robati, Mikara R., Ng, Ashley P., Cory, Suzanne
Format: Article
Language:English
Subjects:
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Animals
Apoptosis
BIM protein
Biochemistry
Biomedical and Life Sciences
Bone marrow
c-Myc protein
Cell Biology
Cell Cycle Analysis
Cells
Clonal deletion
Competition
Flow cytometry
Life Sciences
Lymphocytes
Lymphocytes - metabolism
Lymphocytes T
Lymphoid cells
Lymphoma
Lymphoma - genetics
Lymphoma - pathology
Lymphopoiesis
Malignancy
Medical prognosis
Mice
Mice, Transgenic
Myc protein
Progenitor cells
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Spleen
Stem Cells
Survival analysis
T-Lymphocytes - metabolism
Therapeutic targets
Thymus
Thymus gland
Transgenic animals
Transgenic mice
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Summary:The importance of c-MYC in regulating lymphopoiesis and promoting lymphomagenesis is well-established. Far less appreciated is the vital supporting role of MYC’s relative MNT. Using Rag1Cr e-mediated Mnt deletion in lymphoid progenitor cells, we show here that, during normal T cell development, MNT loss enhances apoptosis, at least in part by elevating expression of the pro-apoptotic BH3-only protein BIM. Moreover, using T lymphoma-prone VavP- MYC transgenic mice, we show that Mnt deletion reduces the pool of pre-malignant MYC-driven T lymphoid cells and abrogates thymic T lymphomagenesis. In addition, we establish that Mnt deletion prevents T lymphoma development in γ-irradiated mice, most likely by enhancing apoptosis of T lymphoid cells repopulating the depleted thymus. Taken together with our recent demonstration that MNT is vital for the survival of MYC-driven pre-malignant and malignant B lymphoid cells, these results suggest that MNT represents an important new drug target for both T and B lymphoid malignancies.
ISSN:1350-9047
1476-5403
DOI:10.1038/s41418-023-01119-y