Mechanisms of relapse in acute leukaemia: involvement of p53 mutated subclones in disease progression in acute lymphoblastic leukaemia

Abstract

Summary Mutations of the p53 tumour suppressor gene are infrequent at presentation of both acute myeloblastic leukaemia (AML) and acute lymphoblastic leukaemia (ALL), being found in between 5-10% of AML and 2-3% of ALL. Here we have studied the frequency of detection of p53 mutations at relapse of both AML and B-precursor ALL. In those patients with detectable mutations at relapse we investigated whether the mutation was detectable at presentation and was thus an early initiating event or whether it had arisen as a late event associated with relapse. Bone marrow samples from 55 adults and children with relapsed AML (n = 41) or ALL (n = 14) were analysed for p53 gene alterations by direct sequencing of exons 5-9. For samples where a p53 mutation was found at relapse, analysis of presentation samples was carried out by direct sequencing of the exon involved, or by allele-specific polymerase chain reaction (PCR) if the mutation could not be detected using direct sequencing. A p53 mutated gene was found at relapse in seven out of 55 cases. The frequency was higher in relapsed ALL (four out of 14 cases; 28.6%) compared to AML (three out of 41 cases; 7.3%). In five out of the seven cases presentation samples were available to study for the presence of the mutation. In two out of two AML patients the p53 mutation was detectable in the presentation sample by direct sequencing. In three ALL patients analysis of presentation material by direct sequencing showed a small mutant peak in one case, the other two being negative despite the sample analysed containing > 90% blast cells. However in both of these patients, the presence of p53 mutation was confirmed in the presentation sample using allele-specific PCR. In one of these patients the emergence of a subclone at relapse was confirmed by clonality analysis using IgH fingerprinting. Our results confirm that in ALL p53 mutations are present in a proportion of patients at relapse. Furthermore cells carrying the mutation are detectable at presentation in a minor clone suggesting that p53 mutations in ALL may be a mechanism contributing to disease relapse.

TP53 mutations are frequent in adult acute lymphoblastic leukemia cases negative for recurrent fusion genes and correlate with poor response to induction therapy

“…Overall, 10 TP53 mutations were identified in the current study: 8 at diagnosis and 2 at relapse. These results confirm previous reports [10][11][12] that TP53 mutations increase at disease reappearance. The number of mutations at relapse is lower than that reported for childhood ALL.…”

TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis

“…6 For TP53 mutations in adult ALL, only a few studies are available that include mostly relapsed cases and small cohorts of patients. 25,26 Thus far, the largest series of adult ALL investigated for TP53 mutations includes 98 adult patients 2 and shows TP53 mutations in 8 patients (8.2%), which is similar to the TP53 mutation frequency in AML at diagnosis and in CLL at the time of progression. 10,11 Furthermore, the results support previous findings of an increase of TP53 mutations at disease reappearance.…”

Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-κB survival pathway signaling

“…Interestingly, in pediatric ALL, the incidence of TP53 mutation is notably low, with less than 5% of tumors at diagnosis harboring detectable mutations. 7,8 Although the rate of mutation at relapse is slightly higher, 9 indicating a role for p53 inactivation in drug resistance, genes other than p53 that impinge on its function, such as ATM, [10][11][12][13][14] MDM2, p21, BCL2, and BAX, [15][16][17][18][19][20][21][22] might be involved in tumor progression. Furthermore, given that the balance between proapoptotic and prosurvival signals is critical in determining cell fate after DNA damage, 5 distinct pathways activated in response to DNA damage may alternatively be deregulated.…”