Renewable tissues exhibit heightened sensitivity to DNA damage, which is thought to result from a high level of p53. However, cell proliferation in renewable tissues requires p53 down-regulation, creating an apparent discrepancy between the p53 level and elevated sensitivity to DNA damage. Using a combination of genetic mouse models and pharmacologic inhibitors, we demonstrate that it is p53-regulated MDM2 that functions together with MDMX to regulate DNA damage sensitivity by targeting EZH2 (enhancer of zeste homolog 2) for ubiquitination/degradation. As a methyltransferase, EZH2 promotes H3K27me3, and therefore chromatin compaction, to determine sensitivity to DNA damage. We demonstrate that genetic and pharmacologic interference of the association between MDM2 and MDMX stabilizes EZH2, resulting in protection of renewable tissues from radio-/chemotherapy-induced acute injury. In cells with p53 mutation, there are diminished MDM2 levels, and thus accumulation of EZH2, underpinning the resistant phenotype. Our work uncovers an epigenetic mechanism behind tissue sensitivity to DNA damage, carrying important translation implications.
A role of tumor suppressive activity of p53 in the tumor microenvironment (TME) has been implicated but remains fairly understudied. To address this knowledge gap, we leveraged our MdmxS314A mice as recipients to investigate how implanted tumor cells incapacitate host p53 creating a conducive TME for tumor progression. We found that tumor cell-associated stress induced p53 downregulation in peritumor cells via a MDMX-Ser314 phosphorylation-dependent manner. As a result, an immunosuppressive TME was developed, as reflected by diminished immune cell infiltration into tumors and compromised macrophage M1 polarization. Remarkably, ablation of MDMX-Ser314 phosphorylation attenuated p53 decline in peritumor cells, which was associated with mitigation of immunosuppression and significant tumor growth delay. Our data collectively uncover a novel role of p53 in regulating tumor immune microenvironment, suggesting that p53 restoration in the TME can be exploited as a potential strategy of anticancer therapy.
T-cell lymphoblastic lymphoma (T-LBL), an aggressive and poorly treated neoplasm of immature T-cell precursors or lymphoblasts, 1 develops more frequently in underage males and a small proportion of adults, 2 and it is typically characterized by a grossly enlarged mediastinum with bone marrow involvement. 3 Published data indicate that hematopoietic stem cell transplantation (HSCT) can provide sustained long-term survival and a considerable cure rate for patients. 4,5 Moreover, HSCT combined with chemotherapy may significantly improve the survival rate of patients with T-LBL. 6 It is well known that HSCT can lead to a series of adverse events such as opportunistic infections or organ rejection syndrome, but rapidly developing parotitis after HSCT is uncommon. Thus far, to the best of our knowledge, only two cases of parotitis after allo-HSCT have been reported, which were associated with parainfluenza virus (PIV) 7 or graft-versus-host disease (GVHD). 8 However, suppurative parotitis after auto-HSCT has not been reported until now. Herein, we present this unusual case and our experiences in its management.
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