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Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic work-up and therapy

Miron Prokocimer, Alina Molchadsky and Varda Rotter

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 a tenth of de-novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to non-mutational p53 abnormalities appear 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 co-existing p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function, but also on the mechanisms underlying non-mutational 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.

  • Submitted February 27, 2017.
  • Accepted June 6, 2017.