TP53 Mutations in Acute Myeloid Leukemia

Abstract

Mutations of the TP53 gene show a low frequency in overall acute myeloid leukemia (AML). However, they were found at frequencies of 60–80 % in complex karyotype AML, and are strongly associated with therapy-related AML. TP53 mutations are considered to represent a separate functional category independent from the typical class I and class II mutations. The mutations are heterogeneous and are distributed across the TP53 gene with clustering of the mutations in exons 5–8. TP53 mutations confer an adverse prognostic impact in patients with AML. High-throughput sequencing facilities are now available for rapid screening for TP53 mutations at diagnosis of AML aiming to identify patients who may have a benefit from early allogeneic hematopoietic stem cell transplantation or other alternative therapeutic approaches.

Conclusions

TP53 mutations seem to represent a separate functional category in AML which have no equivalent to the typical class I or II mutations (Pedersen-Bjergaard et al. 2008; Renneville et al. 2008). The high frequency of TP53 mutations in complex karyotype AML (Haferlach et al. 2008; Rücker et al. 2012) contributes to explain the frequent phenomenon of chemoresistance in this cytogenetic subgroup. Whereas the traditional molecular work-up for detection of the heterogeneous TP53 mutations was highly laborious, investigation of TP53 mutations is considerably facilitated by high-throughput sequencing (Bejar et al. 2011; Jaedersten et al. 2011). A rapid screening for TP53 mutations eventually combined with investigation of the TP53 allele status by FISH and/or array-CGH at diagnosis of the AML can identify high-risk patients who may have a benefit from alternative treatment strategies (e.g., an early allogeneic HSCT or novel strategies targeting the TP53 pathway in clinical studies).