p53 pathway dysfunction is highly prevalent in acute myeloid leukemia independent of TP53 mutational status
TP53 mutations are associated with the lowest survival rates in acute myeloid leukemia (AML). In addition to mutations, loss of p53 function can arise via aberrant expression of proteins that regulate p53 stability and function. We examined a large AML cohort using proteomics, mutational profiling a...
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Veröffentlicht in: | Leukemia 2017-06, Vol.31 (6), p.1296-1305 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | TP53
mutations are associated with the lowest survival rates in acute myeloid leukemia (AML). In addition to mutations, loss of p53 function can arise via aberrant expression of proteins that regulate p53 stability and function. We examined a large AML cohort using proteomics, mutational profiling and network analyses, and showed that (1) p53 stabilization is universal in mutant
TP53
samples, it is frequent in samples with wild-type
TP53
, and in both cases portends an equally dismal prognosis; (2) the p53 negative regulator Mdm2 is frequently overexpressed in samples retaining wild-type
TP53
alleles, coupled with absence of p21 expression and dismal prognosis similar to that of cases with p53 stabilization; (3) AML samples display unique patterns of p53 pathway protein expression, which segregate prognostic groups with distinct cure rates; (4) such patterns of protein activation unveil potential AML vulnerabilities that can be therapeutically exploited. |
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ISSN: | 0887-6924 1476-5551 |
DOI: | 10.1038/leu.2016.350 |