TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

Abstract

Objectives TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence and treatment outcome in TP53 mutated AML/MDS patients in Asian population are scarce. We therefore conducted this study to analyze the prevalence and the treatment outcomes of TP53 mutation in AML and MDS-EB patients. Methods Patients with newly diagnosed AML and MDS-EB were recruited, extraction of deoxyribonucleic acid from bone marrow samples were done and then performing TP53 mutation analysis, using MassArray® System (Agena Bioscience, CA, USA). Results A total of 132 AML/MDS patients were recruited, patients with de novo AML, secondary AML, MDS-EB1, MDS-EB2 and T-AML/MDS were seen in 66, 13, 9, 9 and 3%, respectively. TP53 mutation was found in 14 patients (10.6%), and prevalence of TP53 mutation in T-AML/MDS, secondary AML, de novo AML and MDS-EB patients were 50, 17.6, 9.2 and 8%, respectively. Three patients had double heterozygous TP53 mutation. Mutated TP53 was significantly detected in patients with monosomy and complex chromosome. Common TP53 mutation were R290C, T220C, A249S and V31I which V31I mutation was reported only in Taiwanese patients. Most variant allele frequency (VAF) of TP53 mutation in the study were greater than 40%. Three year-overall survival (OS) in the whole population was 22%, 3y-OS in AML and MDS-EB patients were 22 and 27%, respectively. The 1y-OS in patients with TP53-mutant AML/MDS were shorter than that in TP53 wild-type patients, 14% versus 50%, P = 0.001. In multivariate analysis, factors affecting OS in 132 AML/MDS patients was mutant TP53 (P = 0.023, HR = 1.20–7.02), whereas, WBC count> 100,000/μL (P = 0.004, HR = 1.32–4.16) and complex karyotype (P = 0.038, HR = 1.07–9.78) were associated with shorter OS in AML patients. Discussion In this study, the prevalence of TP53 mutation in de novo AML and MDS-EB patients were low but it had impact on survival. Patients with monosomy or complex karyotype had more frequent TP53 mutation.

Targeting Apoptosis in AML: Where Do We Stand?

“…Where the mutation is absent, as noted in the majority of AML cases, it is possible that apoptosis is blocked by alternate mechanisms [ 32 ]. Intriguingly, patients with a TP53 mutation have a lower-than-expected frequency of mutations in other myeloid-related genes, involving splicing, epigenetics, and signal transduction [ 28 , 33 ]. However, irrespective of TP53 mutational status, many AML cases are characterized by p53 dysfunction, presumably through the alteration of p53-regulatory proteins, resulting in the disruption of apoptosis [ 7 , 34 ].…”

Treatment for a B-cell acute lymphoblastic leukemia patient carrying a rare TP53 c.C275T mutation: A case report

“…p53 mutants not only lose their tumor-suppressing activity but also have disrupted the function of wild-type p53 proteins, which further promotes the progression of tumors ( 26 – 28 ). For example, myelodysplastic syndrome and acute myeloid leukemia patients with TP53 mutations were found to have poor chemotherapy response and short remission period, especially those with biallelic mutations of TP53 and those with complex karyotypes, who were more prone to relapse even after bone marrow transplantation ( 29 , 30 ).…”

A customized mass array panel for BCR::ABL1 tyrosine kinase domain mutation screening in chronic myeloid leukemia

“…In this work, multiplex PCR was performed following our previous protocol for hotspot TP53 mutation analysis [55] . In brief, PCR amplification was performed using a polymerase chain reaction (PCR) primer mix (forward and reverse primers) with 100 nM MgCl 2 solution, 500 μM dNTP, 1x PCR buffer, 0.2 units/μL PCR enzyme, and 10–20 ng of DNA, making up a final volume of 5 μL.…”

“…We recently reported practical laboratory investigation tools for managing patients with CML and established a domestic TKD mutational database of CML patients [54] . Moreover, we have developed a mass array technique that is a straightforward and robust assay for screening TP53 hotspot mutations in patients with acute myeloid leukemia (AML) [55] . In this report, we present customization of the mass array technique for the simultaneous detection of BCR :: ABL1 TKD mutations in patients with CML based on our TKD mutational database and recent ELN guidelines for the management of CML.…”