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Editorials
Therapeutic targeting of mutated p53 in acute lymphoblastic leukemia
Frank N. van Leeuwen
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
E-mail: FRANK N. VAN LEEUWEN - F.N.vanleeuwen@prinsesmaximacentrum.nl
doi:10.3324/haematol.2019.234872
In this issue of Haematologica, Demir and colleagues In relapsed ALL, the frequency of TP53 mutations or
describe a potential novel therapy for TP53-mutated deletions rises to about 10% and represents a strong and 15
acute lymphoblastic leukemia (ALL). TP53, the gene encoding p53, is probably the most studied tumor sup- pressor in cancer biology. In about 50% of all human can- cers, a mutation or deletion of TP53 is observed at some point during tumor development or progression. The high incidence of TP53 loss of function across human tumors relates to its central role as a transcription factor controlling cell cycle regulation in response to DNA dam- age, DNA repair, metabolic regulation, stem cell develop- ment and cell senescence.2 In most hematologic malig- nancies, loss of p53 function is a harbinger of a poor response to therapy, particularly at relapse.3 In ALL, genetic alterations affecting TP53 are surprisingly uncom- mon at diagnosis, with their incidence being less than 5%.4 A notable exception is a rare ALL subtype known as low hypodiploid ALL (32–39 chromosomes), in which there are almost invariably mutations or deletions affect- ing TP53. In about 50% of patients with low hypodiploid ALL, TP53 alterations are also present in somatic cells, suggesting that Li-Fraumeni syndrome, an autosomal dominant disorder involving loss of TP53, somehow favors the development of low hypodiploid ALL in chil- dren.4
independent predictor of treatment failure. TP53 alter- ations result in either a loss of protein expression or the generation of protein variants with (partly) impaired function. About 80% of these TP53 variants are the result of missense mutations that affect DNA binding.3 In most cancers, the TP53 gene behaves as a classical tumor sup- pressor, which means that after mutation of one allele, the second allele is lost at a later stage of the disease. However, such a biallelic loss of function is not always observed in ALL, suggesting that dominant-negative effects or haploinsufficiency contribute to leukemogene- sis or resistance to therapy.5 Regardless of whether a wildtype allele is still present, TP53 mutations or dele- tions in relapsed ALL predict a highly unfavorable response to therapy. Consequently, the International study for treatment of childhood relapsed ALL (IntReALL), a pan-European study group, now recognizes TP53-aberrant ALL relapse as a rare but very high-risk subtype that requires international collaboration in order to design and test novel treatment protocols, which may include drugs targeting p53.
Figure 1. Proposed mechanism of action of APR-246 in TP53-mutated acute lymphoblastic leukemia. Acute lymphoblastic leukemia (ALL) cells expressing mutant p53 are refractory to doxorubicin-induced apoptosis. APR-246 is taken up by cells and metabolized into the reactive electrophile methylene quinuclidinone (MQ). By refolding p53 into an active conformation, MQ restores the apoptosis-inducing effects of doxorubicin. In addition, an increase in oxidative stress brought about by MQ may further enhance apoptosis induction.
In the absence of cellular stress signals, expression of the p53 protein is strictly controlled by MDM2 and its
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haematologica | 2020; 105(1)