![]() ![]() We show that MNT loss enhances apoptosis of developing T lymphoid cells and abrogates T lymphoma development in vavP- MYC transgenic mice and γ-irradiated C57BL/6 mice. We establish, for the first time, that MNT loss reduces the competitive fitness of T (and B) lymphopoiesis. We confirm that MNT loss promotes T cell apoptosis and provide new genetic and biochemical evidence regarding the underlying mechanism. Here, building on earlier studies, we investigate how MNT loss, mediated by a Rag1Cre transgene in lymphoid progenitor cells, impacts normal T cell development and T lymphomagenesis. Many human T cell neoplasms are associated with poor prognosis and new therapeutic approaches are sorely needed. ![]() We recently established that MNT is critical for lymphomagenesis in Eμ-Myc transgenic mice, which model human Burkitt’s lymphoma, and showed that MNT aids MYC by suppressing apoptosis in both pre-malignant and fully malignant B lymphoid cells. MNT, an important member of this MXD ( MA X Dimerization) family of c-MYC antagonists is essential for embryonic development and widely expressed in mammalian tissues. However, MAX also binds several MYC-related transcriptional repressors containing bHLHLZ domains. To activate transcription, MYC heterodimerises with MAX, another ubiquitously expressed basic Helix-Loop-Helix Leucine Zipper (bHLHLZ) protein, and together they bind E-box motifs (CACGTG) in target genes. Hence, genetic defects that impede apoptosis boost MYC’s oncogenic potential, as first revealed by the seminal demonstration that anti-apoptotic BCL-2 synergises with MYC in lymphomagenesis. ![]() However, stressed cells expressing elevated MYC are prone to apoptosis, which serves as a critical restraint on neoplastic transformation. The transcription factor c-MYC (hereafter MYC) controls expression of numerous genes involved in the proliferation, growth, metabolism and DNA damage responses of normal cells in adult tissues and its deregulated over-expression is a major driver of human cancer. 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. 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. 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. Using Rag1Cre-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. Far less appreciated is the vital supporting role of MYC’s relative MNT. The importance of c-MYC in regulating lymphopoiesis and promoting lymphomagenesis is well-established. ![]()
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