Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/t-AML) are late complications of cytotoxic therapy used in the treatment of malignant diseases. The most common subtype of t-AML ( approximately 75% of cases) develops after exposure to alkylating agents, and is characterized by loss or deletion of chromosome 5 and/or 7 [-5/del(5q), -7/del(7q)], and a poor outcome (median survival 8 months). In the University of Chicago's series of 386 patients with t-MDS/t-AML, 79 (20%) patients had abnormalities of chromosome 5, 95 (25%) patients had abnormalities of chromosome 7, and 85 (22%) patients had abnormalities of both chromosomes 5 and 7. t-MDS/t-AML with a -5/del(5q) is associated with a complex karyotype, characterized by trisomy 8, as well as loss of 12p, 13q, 16q22, 17p (TP53 locus), chromosome 18, and 20q. In addition, this subtype of t-AML is characterized by a unique expression profile (higher expression of genes) involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), loss of expression of IRF8, and overexpression of FHL2. Haploinsufficiency of the RPS14, EGR1, APC, NPM1, and CTNNA1 genes on 5q has been implicated in the pathogenesis of MDS/AML. In previous studies, we determined that Egr1 acts by haploinsufficiency and cooperates with mutations induced by alkylating agents to induce myeloid leukemias in the mouse. To identify mutations that cooperate with Egr1 haploinsufficiency, we used retroviral insertional mutagenesis. To date, we have identified two common integration sites involving genes encoding transcription factors that play a critical role in hematopoiesis (Evi1 and Gfi1b loci). Of note is that the EVI1 transcription factor gene is deregulated in human AMLs, particularly those with -7, and abnormalities of 3q. Identifying the genetic pathways leading to t-AML will provide new insights into the underlying biology of this disease, and may facilitate the identification of new therapeutic targets.
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PMID:Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia. 1995 52

Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P<0.01) among the patients with therapy-related disease. In mutational analysis, TP53 alteration was the most common abnormality in patients with therapy-related disease (n=18: 30%). Interestingly, the presence of mutations in TP53 or in any other of the high-risk genes (EZH2, ETV6, RUNX1, ASXL1: n=29: 48%) did not significantly affect either overall survival or relapse-free survival. Allogeneic stem-cell transplantation is, therefore, a curative treatment for patients with therapy-related myelodysplastic syndrome, conferring a similar long-term survival to that of patients with de novo disease despite higher-risk features. While TP53 alteration was the most common mutation in therapy-related myelodysplastic syndrome, the finding was not detrimental in our case-series.
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PMID:Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status. 2919 30