Transient enhancement of p53 activity protects from radiation-induced gastrointestinal toxicity.

Gastrointestinal (GI) syndrome is a serious side effect and dose-limiting toxicity observed in patients undergoing lower-abdominal radiotherapy. Previous mouse studies show that p53 gene dosage determines susceptibility to GI syndrome development. However, the translational relevance of p53 activity has not been addressed. Here, we used a knock-in mouse in which the p53-Mdm2 negative feedback loop is genetically disrupted. These mice retain biallelic p53 and thus, normal basal p53 levels and activity. However, due to the lack of p53-mediated Mdm2 transcription, irradiated Mdm2P2/P2 mice exhibit enhanced acute p53 activity, which protects them from GI failure. Intestinal crypt cells residing in the +4 and higher positions exhibit decreased apoptosis, increased p21 expression, and hyperproliferation to reinstate intestinal integrity. Correspondingly, pharmacological augmentation of p53 activity in wild-type mice with an Mdm2 inhibitor protects against GI toxicity without affecting therapeutic outcome. Our results suggest that transient disruption of the p53-Mdm2 interaction to enhance p53 activity could be a viable prophylactic strategy for alleviating GI syndrome in patients undergoing radiotherapy.

Synergistic and additive effect of retinoic acid in circumventing resistance to p53 restoration.

TP53 mutations occur in ∼50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of p53R172H -mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.

Tumorigenesis promotes Mdm4-S overexpression.

Disruption of the p53 tumor suppressor pathway is a primary cause of tumorigenesis. In addition to mutation of the p53 gene itself, overexpression of major negative regulators of p53, MDM2 and MDM4, also act as drivers for tumor development. Recent studies suggest that expression of splice variants of Mdm2 and Mdm4 may be similarly involved in tumor development. In particular, multiple studies show that expression of a splice variant of MDM4, MDM4-S correlates with tumor aggressiveness and can be used as a prognostic marker in different tumor types. However, in the absence of prospective studies, it is not clear whether expression of MDM4-S in itself is oncogenic or is simply an outcome of tumorigenesis. Here we have examined the role of Mdm4-S in tumor development in a transgenic mouse model. Our results suggest that splicing of Mdm4 does not promote tumor development and does not cooperate with other oncogenic insults to alter tumor latency or aggressiveness. We conclude that Mdm4-S overexpression is a consequence of splicing defects in tumor cells rather than a cause of tumor evolution.

Mdm proteins: critical regulators of embry ogenesis and homeostasis.

Mdm2 and Mdm4 are negative regulators of the tumor suppressor p53; hence, this relationship is the focus of many cancer related studies. A multitude of experiments across various developmental stages have been conducted to explore the tissue-specific roles of these proteins in the mouse. When Mdm2 or Mdm4 are deleted in the germline or specific tissues, they display different phenotypic defects, some of which lead to embryonic lethality. Mdm2 loss is often more deleterious than loss of its homolog Mdm4 All tissues experience activation of p53 target genes upon loss of Mdm2 or Mdm4; however, the degree to which the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological phenotypes. Therefore, a need for further understanding of how these proteins regulate p53 activity is warranted, as therapeutic targeting of the p53 pathway is rapidly evolving and gaining attention in the field of cancer research. In this review, we discuss the tissue-specificity of Mdm proteins in regulating p53 and expose the need for investigation at the cell-specific level.

The changing mutational landscape of acute myeloid leukemia and myelodysplastic syndrome.

UNLABELLED: Over the past few years, large-scale genomic studies of patients with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have unveiled recurrent somatic mutations in genes involved in epigenetic regulation (DNMT3A, IDH1/2, TET2, ASXL1, EZH2 and MLL) and the spliceosomal machinery (SF3B1, U2AF1, SRSF2, ZRSR2, SF3A1, PRPF40B, U2AF2, and SF1). The identification of these mutations and their impact on prognostication has led to improvements in risk-stratification strategies and has also provided new potential targets for the treatment of these myeloid malignancies. In this review, we discuss the most recently identified genetic abnormalities described in MDS and AML and appraise the current status quo of the dynamics of acquisition of mutant alleles in the pathogenesis of AML, during the transformation from MDS to AML, and in the context of relapse after conventional chemotherapy. IMPLICATIONS: Identification of somatic mutations in AML and MDS suggests new targets for therapeutic development.