Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: Projections on diagnostic workup and therapy

Miron Prokocimer, Alina Molchadsky, Varda Rotter*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

122 Scopus citations

Abstract

The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices.

Original languageEnglish
Pages (from-to)699-712
Number of pages14
JournalBlood
Volume130
Issue number6
DOIs
StatePublished - 10 Aug 2017

Funding

FundersFunder number
Israel Cancer Research Fund
Ohio Academy of Science
Stowers Institute for Medical Research
Maine Medical Center Research Institute
Weizmann Institute of Science
Canada Research Chairs
Israel Science Foundation
Israeli Centers for Research Excellence

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