The p53 tumor suppressor gene and gene product are among the most diverse and complex molecules involved in cellular functions. Genetic alterations within the p53 gene have been shown to have a direct correlation with cancer development and have been shown to occur in nearly 50% of all cancers. p53 mutations are particularly common in skin cancers and UV irradiation has been shown to be a primary cause of specific 'signature' mutations that can result in oncogenic transformation. There are certain 'hot-spots' in the p53 gene where mutations are commonly found that result in a mutated dipyrimidine site. This review discusses the role of p53 from normal function and its dysfunction in pre-cancerous lesions and non-melanoma skin cancers. Additionally, special situations are explored, such as Li-Fraumeni syndrome in which there is an inherited p53 mutation, and the consequences of immune suppression on p53 mutations and the resulting increase in non-melanoma skin cancer in these patients. MOLECULAR INDICATIONS OF THE ROLE OF p53 IN CANCERThere are multiple genetic alterations that have been shown to have a direct correlation with cancer development. Majority of these mutations can be found within three categories of genes: proto-oncogenes, tumor suppressor genes, or DNA repair genes. A mutation in one of these groups or any combination can cooperate to induce a neoplastic condition. The protooncogenes act as a crucial growth regulators in normal cell division, while the tumor suppressor genes act as negative growth regulators. The p53 tumor suppressor gene is involved in the cell cycle arrest and activation of programmed cell death (Hartwell and Weinert, 1989;Lane, 1992). Mutations in the p53 gene have been detected in 50% of all human cancers and in almost all skin carcinomas (Basset-Seguin et al., 1994). p53 codes for a 53-kDa phosphoprotein involved in gene transcription and control of the cell cycle by coordinating transcriptional control of regulatory genes (Levine et al., 1991;Vogelstein and Kinzler, 1992;Harris, 1996). Human p53 is a highly conserved 11 exon gene that is located on the short arm of chromosome 17 (Lamb and Crawford, 1986) that is about 20 Kb in size. The p53 protein forms tetramers through interactions between C-terminal regions of the protein. These tetramers can then recognize specific binding sites on target genes and stimulate their activation. Mutant forms of p53 rarely exhibit mutations in the oligomerization region, but rather have mutations in the DNA binding domain.Majority of carcinomas have missense mutations that produce a full-length protein with altered function. Often the other allele is lost resulting in loss of heterozygosity (LOH), which is particularly high (40-80%) in carcinomas of the colon, lung, and bladder (Greenblatt et al., Correspondence to: Honnavara N. Ananthaswamy. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscrip...

The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150 IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV <350 IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P = .02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV <350 IU/mL and those who started at CMV >350 IU/mL (44% versus 57%; P = .42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P = .001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P = .02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P <.0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150 IU/mL is associated with a >80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350 IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.

Key Points• RAS/MEK/ERK signaling is memory stage-dependent in human T cells, conferring susceptibility to alloreactive T-cell selective inhibition.• MEK inhibitors selectively inhibit alloreactive but not herpesvirus-specific human T cells and inhibit murine GVHD.Immunosuppressive strategies currently used in hematopoietic stem cell transplantation reliably decrease graft-versus-host disease (GVHD) rates, but also impair pathogenspecific immunity. Experimental transplant studies indicate that GVHD-initiating alloreactive T cells reside primarily in naive and central memory T-cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor kinase (RAS/MEK/ERK) pathway is preferentially activated in naive and central memory human T cells, we hypothesized that MEK inhibitors would preferentially inhibit alloreactive T cells, while sparing more differentiated virus-specific T cells. Confirming our hypothesis, we found that MEK inhibitors including selumetinib preferentially inhibited cytokine production and alloreactivity mediated by naive and central memory human CD4 1 and CD8 1 T cells while sparing more differentiated T cells specific for the human herpesviruses cytomegalovirus and Epstein-Barr virus. We then demonstrated that short-term posttransplant administration of selumetinib in a major histocompatibility complex major-and minor-mismatched murine model significantly delayed the onset of GVHD-associated mortality without compromising myeloid engraftment, demonstrating the in vivo potential of MEK inhibitors in the setting of hematopoietic stem cell transplantation. These findings demonstrate that targeting memory-dependent differences in T-cell signaling is a potent and selective approach to inhibition of alloreactivity. (Blood. 2013;121(23):4617-4626)

Reduced intensity conditioning (RIC) regimens have the potential to decrease transplant-related morbidity and mortality. However, engraftment failure has been prohibitively high after RIC unrelated umbilical cord blood transplantation (UCBT) in chemotherapy-naïve children with non-malignant diseases (NMD). Twenty-two children with a median age of 2.8 years, many with severe comorbidities and prior viral infections were enrolled in a novel RIC protocol consisting of hydroxyurea, alemtuzumab, fludarabine, melphalan and thiotepa followed by single UCBT. Patients were transplanted for inherited metabolic disorders (N=8), primary immunodeficiencies (N=9), hemoglobinopathies (N=4) and Diamond Blackfan anemia (N=1). Most UCB units were HLA-mismatched with median infused total nucleated cell dose of 7.9 × 107/kg. No serious organ toxicities were attributable to the regimen. The cumulative incidence of neutrophil engraftment was 86.4% (95% confidence interval [CI], 65%–100%) in a median of 20 days, with the majority sustaining >95% donor chimerism at 1 year. Cumulative incidence of acute graft-versus-host disease (GVHD) grades II–IV and III–IV by day 180 was 27.3% (95% CI, 8.7%–45.9%) and 13.6% (95 CI, 0%–27.6%), respectively. Cumulative incidence of extensive chronic GVHD was 9.1% (95% CI, 0%–20.8%). The primary causes of death were viral infections (N=3), acute GVHD (N=1) and transfusion reaction (N=1). One-year overall and event-free survivals were 77.3% (95% CI, 53.7%–89.8%) and 68.2% (95% CI, 44.6%–83.4%) with 31 months median follow-up. This is the first RIC protocol demonstrating durable UCB engraftment in children with NMD. Future risk-based modifications of this regimen could decrease the incidence of viral infections. (www.clinicaltrials.gov/NCT00744692)